Toward Understanding the Molecular Pathology of Huntington's Disease

Cheryl L Wellington; Ryan R Brinkman; John R O'Kusky; Michael R Hayden

doi:10.1111/j.1750-3639.1997.tb00897.x

. 2008 Jan 28;7(3):979–1002. doi: 10.1111/j.1750-3639.1997.tb00897.x

Toward Understanding the Molecular Pathology of Huntington's Disease

Cheryl L Wellington ¹, Ryan R Brinkman ², John R O'Kusky ³, Michael R Hayden ^1,^2,^✉

PMCID: PMC8098409 PMID: 9217979

Abstract

Huntington's Disease (HD) is caused by expansion of a CAG trinucleotide beyond 35 repeats within the coding region of a novel gene. Recently, new insights into the relationship between CAG expansion in the HD gene and pathological mechanisms have emerged. Survival analysis of a large cohort of affected and at‐risk individuals with CAG sizes between 39 and 50 repeats have yielded probability curves of developing HD symptoms and dying of HD by a certain age. Animals transgenic for the first exon of huntingtin with large CAG repeats lengths have been reported to have a complex neurological phenotype that bears interesting similarities and differences to HD. The repertoire of huntingtin‐inter‐acting proteins continues to expand with the identification of HIP1, a protein whose yeast homologues have known functions in regulating events associated with the cytoskeleton. The ability of huntingtin to interact with two of its four known protein partners appears to be influenced by CAG length. Caspase 3 (apopain), a key cysteine protease known to play a seminal role in neural apoptosis, has also been demonstrated to specifically cleave huntingtin in a CAG length‐dependent manner. Many of these features are combined in a model suggesting mechanisms by whi h the pathogenesis of HD may be initiated. The development of appropriate in vitro and animal models for HD will allow the validity of these models to be tested.

Full Text

The Full Text of this article is available as a PDF (2.4 MB).

References

1. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12: 366–375. [DOI] [PubMed] [Google Scholar]
2. Andrade MA, Bork P (1995) HEAT repeats in the Huntington's disease protein. Nature Genet 11: 115–116. [DOI] [PubMed] [Google Scholar]
3. Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA, Graham RK, Hayden MR (1993) The relationship between trinucleotide repeat (CAG) length and clinical features of Huntington disease. Nature Genet 4: 398–403. [DOI] [PubMed] [Google Scholar]
4. Banfi S, Servadio A, Chung M‐y, Kwiatkowski TJ Jr., McCall AE, Duvick LA, Shen Y, Roth EJ, Orr HT, Zoghbi HY (1994) Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nature Genet 7: 513–519. [DOI] [PubMed] [Google Scholar]
5. Barron L, Warner J, Porteous M, Holloway S, Simpson S, Davidson R, Brock DJH (1993) A study of the Huntington's disease associated trinucleotide repeat in the Scottish population. J Med Genet 30(12): 1003–1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses Ann Neurol 31: 119–130. [DOI] [PubMed] [Google Scholar]
7. Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38: 357–366. [DOI] [PubMed] [Google Scholar]
8. Beal MF, Brouillet E, Jenkins BG, Ferrante FJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993) Neurochemical and histologic characterization of striatal excilotoxic lesions produced by the mitochondrial toxin 3‐nitroproprionic acid. J Neuro 13(10): 4181–4192. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Beal MF, Ferrante RJ, Swartz KJ, Kowall NW (1991) Chronic quinclinic acid lesions in rats closely resemble Huntington's cisease. J Neurosci 11: 1649–1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Beal MF, Hyman BT, Koroshetz W (1993) Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases TINS 17(3): 107–108. [DOI] [PubMed] [Google Scholar]
11. Beal MF, Lowall NW, Swartz KJ, Ferrante RJ, Martin JB (1989) Differential sparing of somatostatin‐neuropeptide Y and cholinergic neurons following striatal excitotoxin lesions. Synapse 3: 38–47. [DOI] [PubMed] [Google Scholar]
12. Behrens MI, Koh J, Canzoniero LMT, Sensi SL, Csemansky CA, Choi DW (1995) 3‐Nitroproprionic acid induces apoptosis in cultured striatal and cortical neurons. Neuro Report 6(3): 545–548. [DOI] [PubMed] [Google Scholar]
13. Benitez J, Fernandez E, Garcia Ruiz P, Robledo M, Ramos C, Yebenes J (1994) Trinucleotide (CAG) repeat expansion in chromosomes of Spanish patients with Huntington's disease. Hum Genet 94: 563–564. [DOI] [PubMed] [Google Scholar]
14. Boldin MP, Goncharov TM, Golstev YV, Wallach D (1996) Involvement of MACH, a novel MORT/FADD‐interacting protease, in Fas/Apo‐1‐ and TNF receptor‐induced cell death. Cell 85: 803–815. [DOI] [PubMed] [Google Scholar]
15. Borlongan CV, Koutouzis TK, Freeman TB, Cahill DW, Sanberg PR (1995) Behavioral pathology induced by repeated systemic injections of 3‐nitropropionic acid mimics the motoric symptoms of Huntington's disease. Brain Research 697: 254–257. [DOI] [PubMed] [Google Scholar]
16. Borlongan CV, Koutouzis TK, Randall TS, Freeman TB, Cahill DW, Sandberg PR (1995) Systemic 3‐nitropropionic acid: behavioral deficits and striatal damage in adult rats. Brain Research Bulletin 36(6): 549–556. [DOI] [PubMed] [Google Scholar]
17. Bowling AC, Mutisya EM, Walker LC, Price DL, Cork LC, Beal MF (1993) Age‐dependent impairment of mitochondrial function in primate brain. J Neurochem 60: 1964–1967. [DOI] [PubMed] [Google Scholar]
18. Brancolini C, Benedetti M, Schneider C (1995) Microfilament reorganization during apoptosis: the role of Gas2, a possible substrate for ICE‐like proteases. EMBO Journal 14: 5179–5190. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Brinkman RR, Mezei MM, Thielmann J, Almqvist E, Hayden MR (1997) The likelihood of being affected with Huntington disease by a particular age for a specific CAG size. Am J Hum Genet 60: 1202–1210. [PMC free article] [PubMed] [Google Scholar]
20. Brouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy‐Willig A, Kowall NW, Beal MF (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Prcc Natl Acad Sci USA 92: 7105–7109. [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Brouillet E, Jenkins BG, Hyman BT, Ferrante RJ, Kowall NW, Srivastava R, Roy DS, Rosen BR, Beal MF (1993) Age‐dependent vulnerability of the striatum to the mitochondrial toxin 3‐nitropropionic acid. J Neurochem 60: 356–359. [DOI] [PubMed] [Google Scholar]
22. Burke JR, Enghild JJ, Margin ME, Joy Y‐S, Myers RM, Roses AD, Vance JM, Strittmatter WJ (1996) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Genet 2(3): 347–350. [DOI] [PubMed] [Google Scholar]
23. Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HT (1995) SCA1 Transgenic Mice: A Model for Neurodegeneration Caused by an Expanded CAG Trinucleotide Repeat. Cell 82: 937–948. [DOI] [PubMed] [Google Scholar]
24. Cammarata S, Caponnetto C, Tabaton M (1993) Ubiquitin‐reactive neurites in cerebral cortex of subjects with Huntington's chorea: a pathological correlate of dementia Neuro Lett 156: 96–98. [DOI] [PubMed] [Google Scholar]
25. Casciola‐Rosen LA, Grant JA, Rosen A (1995) DNA‐dependent protein kinase is one of a subset of autoanti‐gens specifically cleaved early during apoptosis. J Exp Med 182: 1625–1634. [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Ness KV, Greenstreet TA, March CJ, Krorheim SR, Druck T Cannizzaro LA, Huebner K, Black RA (1992) Molecular cloning of the interlenkin‐1β converting enzyme. Science 256: 97–100. [DOI] [PubMed] [Google Scholar]
27. Chen Z, Niles EG, Pickart CM (1991) Isolation of a cDNA encoding a mammalian multiubiquitinating enzyme (E225K) and overexpression of the functional enzyme in Escherichia coli. J Biol Chem 266: 15698–15704. [PubMed] [Google Scholar]
28. Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM (1997) Interaction of CED‐4 with CED‐3 and CED‐9: A molecular framework for cell death. Science 275: 1122–1126. [DOI] [PubMed] [Google Scholar]
29. Claes S, Van Zand K, Legius E, Dom R, Malfroid M, Baro F, Godderis J, Cassiman J‐J (1995) Correlations between triplet repeat expansion and clinical features in Huntington's disease. Archives of Neurology 52: 749–753. [DOI] [PubMed] [Google Scholar]
30. Coles CJ, Edmonson DE, Singer TP (1979) Inactivation of succinate dehydrogenase by 3‐nitropropionate. J Biol Chem 254(12): 5141–5167. [PubMed] [Google Scholar]
31. Corral‐Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC (1992) Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet 2: 324–329. [DOI] [PubMed] [Google Scholar]
32. Cortopassi GA, Shibata D, Soong N‐W, Arnheim N (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 89: 7370–7374. [DOI] [PMC free article] [PubMed] [Google Scholar]
32b. Cosulich SC, Green S, Clarke PR (1996) Bcl‐2 regulates activation of apoptotic proteases in a cell‐free system. Curr Biol 6(8): 997–1005. [DOI] [PubMed] [Google Scholar]
33. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative diseases. Ann Neurol 38: 357–366. [DOI] [PubMed] [Google Scholar]
34. Crauford D, Dodge A (1993) Mutation size and age at onset in Huntington's disease. J Med Genet 30: 1008–1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Cryns VL, Bergeron L, Zhu H, Li H, Yuan J (1996) Specific cleavage of alpha‐fodrin during Fas‐ and tumor necrosis factor‐induced apoptosis is mediated by an interleukin‐beta‐converting enzyme/CED‐3 protease distinct from the poly(ADP‐ribose)polymerase protease. J Biol Chem 271(49): 31277–31282. [DOI] [PubMed] [Google Scholar]
36. Dawburn D, De Quidt ME, Emson PC (1985) Survival of basal ganglia neuropeptide Y‐somatostatin neurones in Huntington's disease. Brain Res 340: 251–260. [DOI] [PubMed] [Google Scholar]
37. Dawson VL, Kizushi VM, Huang PL, Snyder SH, Dawson TM (1996) Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase ‐ deficient mice. J Neuro 16(8): 2479–2487. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. de Grey ADNJ (1997) A proposed refinement of the mitochondrial free radical theory of aging. BioEssays 19: 161–167. [DOI] [PubMed] [Google Scholar]
39. De Rooij KE, De Koning Gans PA, Skraastad MI, Belfroid RD, Vegter‐van der Vlis M, Roos RA, Bakker E, van Ommen GJ, Den Dunnen JT, Losekoot M (1993) Dynamic mutation in Dutch Huntington's disease patients: increased paternal repeat instabilities extending to within the normal size range. J Med Genet 30(12): 996–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Deshaies RJ (1995) Make it or break it: the role of ubiquitin‐dependent proteolysis in cellular regulation. Trends Cell Biol 5: 428–434. [DOI] [PubMed] [Google Scholar]
41. Dragunow M, Faull RLM, Lawlor P, Beihartz EJ, Singleton K, Walker EB, Mee E (1995) In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Clin Neurosci Neuropath 6: 1053–1057. [DOI] [PubMed] [Google Scholar]
41b. Duan H, Chinnaiyan AM, Hudson PC, Wing JP, He WW, Dixit VM (1996) ICE‐LAP3, a novel mammalian homo‐logue of the caenorhaloditis elegans cell death protein CED‐3 is activated during Fas‐ and Tumor necrosis factor‐induced apoptosis. J Biol Chem 271: 1621–1625. [DOI] [PubMed] [Google Scholar]
43. Duan H, Orth K, Chinnaiyan AM, Poirier GG, Froelich CJ, He W‐W, Dixit VM (1996) ICE‐LAP6, a novel member of the ICE‐CED‐3 gene family, is activated by the cytotoxic T cell protease granzyme B‐. J Biol Chem 271(28): 16720–16724. [DOI] [PubMed] [Google Scholar]
44. Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M, Gray J, Conneally P, Young A, Penney J, Hollingsworth Z, Shoulson I, Lazzarini A, Falek A, Koroshetz W, Sax D, Bird E, Vonsattel J, Bonilla E, Alvir J, Bickham Conde J, Cha J‐H, Dure L, Gomez F, Ramos M, Sanchez‐Ramos J, Snodgrass S, de Young M, Wexler N, Moscowitz C, Penchaszadeh G, MacFarlane H, Anderson M, Jenkins B, Srinidhi J, Barnes G, Gusella J, MacDonald M (1993) Trinucleotide repeat length instability in Huntington disease. Nature Genet 4: 387–392. [DOI] [PubMed] [Google Scholar]
45. Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, Ge P, Vonsattel J‐P, Gusella JF, Joyner AL, MacDonald ME (1995) Inactivation of the Mouse Huntington's Disease Gene Homolog Hdh. Science 269: 407–410. [DOI] [PubMed] [Google Scholar]
46. Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cell 44: 817–829. [DOI] [PubMed] [Google Scholar]
47. Erecinska M, Dagani F (1990) Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes. J Gen Physiol 95(4): 591–616. [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Erecinska M, Nelson D (1994) Effects of 3‐nitropropionic acid on synaptosomal energy and transmitter metabolism: relevance to neurodegenerative brain diseases. J Neurochem 63(3): 1033–1041. [DOI] [PubMed] [Google Scholar]
49. Farrow SN, Brown R (1996) New members of the Bcl‐2 family and their protein partners. Curr Opin Genet Devel 6: 45–49. [DOI] [PubMed] [Google Scholar]
50. Faucheu C, Blanchet AM, Collard‐Dutilleul V, Lalanne JL, Diu‐Hercend A (1996) Identification of a cysteine protease closely related to interieukin‐1 beta‐converting enzyme. Eur J Biochem 236(1): 207–213. [DOI] [PubMed] [Google Scholar]
51. Faucheu C, Diu A, Chang AWE, Blanchet A‐M, Miossec C, Hervé F, Collard‐Dutilieul V, Gu Y, Aldape RA, Lippke JA, Rocher C, Su MS‐S, Livingston DJ, Hercend T, Lalanne J‐L (1995) A novel human protease similar to the interleukin‐1beta converting enzyme induces apoptosis in transfected cells. EMBO Journal 14(9): 1914–1922. [DOI] [PMC free article] [PubMed] [Google Scholar]
52. Fernandes‐Alnemri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (1996) In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD‐like domains. Proc Natl Acad Sci USA 93: 7464–7469. [DOI] [PMC free article] [PubMed] [Google Scholar]
54. Fernandes‐Alremri T, Litwack G, Alnemri ES (1994) CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein CED‐3 and mammalian interleukin‐1 beta converting enzyme. J Biol Chem 270: 30761–30764. [PubMed] [Google Scholar]
55. Fernandes‐Alnemri T, Takahashi A, Armstrong R, Krebs J, Fritz L, Tomaselli KJ, Wang L, Yu Z, Croce CM, Salveson G, Earnshaw WC, Litwack G, Alnemri ES (1995) Mch3, A novel human E. poptotic cysteine protease highly related to CPP32. Cancer Research 55(24): 6045–6052. [PubMed] [Google Scholar]
56. Ferrante RJ, Kowall NW, Beal MF, Richardson EP, Jr. , Bird ED, Martin JB (1985) Selective sparing of a class of striatal neurons in Huntington's disease. Science 230: 561–563. [DOI] [PubMed] [Google Scholar]
57. Fletcher CF, Lutz CM, O'Sullivan TN, Shaughnessy JD Jr., Hawkes R, Frankel WN, Copeland NG, Jenkins NA (1996) Absence epilepsy in Tottering mutant mice is associated with calcium channel defects. Cell 87: 607–617. [DOI] [PubMed] [Google Scholar]
58. Fox JB, Dandliker WB (1956) A study of some of the physical properties of glyceraldehyde‐3‐phosphate dehydrogenase. J Biol Chem 218: 53–57. [PubMed] [Google Scholar]
59. Freese A, DiFiglia M, Koroshetz M, Beal MF, Martin JB (1990) Characterization and mechanism of glutamate neurotoxicity in primary striatal cultures. Brain Research 521:254–264. [DOI] [PubMed] [Google Scholar]
60. Goldberg YP, Andrew SE, Clarke LA, Hayden MR (1993) A PCR methcd for accurate assessment of trinucleotide repeat expansion in Huntington disease. Hum Mol Genet 2(6): 635–636. [DOI] [PubMed] [Google Scholar]
61. Goldberg YP, Kalchman MA, Metzler M, Nasir J, Zeisler J, Graham R, Koide HB, O'Kusky J, Sharp AH, Ross CA, Jirik F, Hayden MR (1996) Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript. Hum Mol Genet 5(2): 177–185. [DOI] [PubMed] [Google Scholar]
62. Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Gromm M, Kazemi‐Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR (1996) Cleavage of nuntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet 13: 442–449. [DOI] [PubMed] [Google Scholar]
63. Gould DH, Gustine DL (1982) Basal ganglia degeneration, myelin alterations, and enzyme inhibition induced in mice by the plant toxin 3‐nitropropionic acid. Neuropathol Appl Neurobiol 8: 377–393. [DOI] [PubMed] [Google Scholar]
64. Gould DH, Wilson MP, Hamar DW (1985) Brain enzyme and clinical alterations induced in rats and mice by nitroaliphatic toxicants. Toxicol Lett 27: 83–89. [DOI] [PubMed] [Google Scholar]
65. Graveland GA, Williams RS, DiFiglia M (1985) A golgi study of the human neostriatum: neurons and afferent fibers. J Comp Neurol 234: 317–333. [DOI] [PubMed] [Google Scholar]
66. Greidinger EL, Miller DK, Yamin TT, Casciola‐Rosen L, Rosen A (1996) Sequential activation of three distinct ICE‐like activities in Fas‐ligated Jurkat cells. FEBS Letters 390(3): 299–303. [DOI] [PubMed] [Google Scholar]
67. Gross NJ, Getz GS, Rabinowitz M (1969) Apparent turnover of mitochondrial deoxyribonucleic acid and mitochondrial phospholipids in the tissues of the rat. J Biol Chem 244: 1552–1562. [PubMed] [Google Scholar]
68. Gu M, Gash MT, Mann VM, Javoy‐Agid F, Cooper JM, Schapira HV (1996) Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 39: 172–177. [DOI] [PubMed] [Google Scholar]
69. Hacker G, Vaux DL (1995) A sticky business. Curr Biol 5(6): 622–624. [DOI] [PubMed] [Google Scholar]
70. Harman D (1972) The biologic clock: the mitochondria J Am Geriatr Soc 20: 145–147. [DOI] [PubMed] [Google Scholar]
71. Harper PS (1991) Huntington's Disease, W. B. Saunders: London . [Google Scholar]
72. Harris JJ, Perham RN (1963) Studies on glyceraldehyde‐3‐phosphate dehydrogenases. Biochem J 89: 60–64. [Google Scholar]
73. Hayden MR (1981) Huntington's chorea, Springer‐Verlag: London, Berlin, Heidelberg . [Google Scholar]
74. Hayden MR (1991) Huntington Disease. In: Textbook of Internal Medicine, Kelley WN (ed.), 2nd Edition, pp. 2179–2181, J. B. Lippincott Co.: Philadelphia . [Google Scholar]
75. Hedreen JC, Folstein SE (1995) Early loss of neostriatal striosome neurons in Huntington's disease. J Neuropathol Exp Neurol 54: 105–120. [DOI] [PubMed] [Google Scholar]
76. Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM, Kruse K (1996) The clinical and molecular spectrum of androgen insensitivity syndromes. Am J Med Genet 63: 218–222. [DOI] [PubMed] [Google Scholar]
77. Holtzman DA, Yang S, Drubin DG (1993) Synthetic‐lethal interactions identify two novel genes, SLA1 and SLA2, that control membrane cytoskeleton assembly in Saccharomyces cerevisiae. J Cell Biol 122(3): 635–644. [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Hope BT, Michael GJ, Knigge KM, Vincent SR (1991) Neuronal NADPH‐diaphorase is a nitric oxide synthase. Proc Natl Acad Sci USA 88: 2811–2814. [DOI] [PMC free article] [PubMed] [Google Scholar]
79. Huitorel P, Pantoloni D (1985) Bundling of microtubules by glyceraldehyde‐e‐phosphate dehydrogenase and its modulation by ATP. Eur J Biochem 150: 265–269. [DOI] [PubMed] [Google Scholar]
80. Huntington Study Group (1995) Huntington Study Group (HSG) policy on non‐disclosure of CAG trinucleotide repeat length (CAGn) genetic (DNA) information as formulated by the HSG Committee of Michael Conneally, Kimberly Quaid, Nancy Wexler and the HSG Executive Committee (Anne Young, John Penney, Dennis Choi, Karl Kieburtz, David Oakes, Ira Shoulson ‐ Chair) and as reviewed and approved by the HSG members (December 3, 1994 and February 13, 1995), (UnPub).
81. Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971–983. [DOI] [PubMed] [Google Scholar]
82. Huntington G (1872) On chorea. Med Surg Rep 26: 317–321. [Google Scholar]
83. Iked A H, Yamaguchi M, Sugai S, Aze Y, Narurniya S, Kakizuka A (1996) Expanded polyglutamine in the Machado‐Joseph disease protein induces cell death in vitro and in vivo. Nature Genet 13(2): 196–202. [DOI] [PubMed] [Google Scholar]
84. Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR (1993) Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology 43(12): 2689–2695. [DOI] [PubMed] [Google Scholar]
85. Jodice C, Malaspina P, Persichetti F, Novelletto A, Spadaro M, Giunti P, Morocutti C, Terrenato L, Harding AE, Frontali M (1994) Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia 1. Am J Hum Genet 54: 959–965. [PMC free article] [PubMed] [Google Scholar]
86. Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR (1996) Huntingtin is ubiquitinated and interacts with a specific ubiquitin conjugated enzyme. J Biol Chem 271 (32): 19385–19394. [DOI] [PubMed] [Google Scholar]
87. Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, Kazemi‐Esfarjani P, Lynn FC, Wellington C, Metzler M, Goldberg YP, Kanazawa I, Gietz RD, Hayden MR (1997) HIP1, a human homolog of S. cerevisiae Sla2p, interacts with membrane‐associated huntingtin in the brain. Nature Genet 16: 44–53. [DOI] [PubMed] [Google Scholar]
88. Kamens J, Paskind M, Hugunin M, Talanian RV, Allen H, Banach D, Bump N, Hackett M, Johnston CG, Li P, Mankovich JA, Terranova M, Ghayur T (1995) Identification and characterization of ICH‐2, a novel member of the interleukin‐1 beta‐converting enzyme family of cysteine proteases. J Biol Chem 270(25): 15250–15256. [DOI] [PubMed] [Google Scholar]
88b. Kluck RM, Bossy‐Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: aprimary site for Bcl‐2 regulation of apoptosis. Science 275: 1132–1136. [DOI] [PubMed] [Google Scholar]
89. Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, Saito M, Tomoda A, Miike T, Naito H, Ikuta F, Tsuji S (1994) Unstable expansion of CAG repeat in hereditary dentatorubral‐pallidoluysian atrophy (DRPLA). Nature Genet 6: 9–13. [DOI] [PubMed] [Google Scholar]
90. Komure O, Sano A, Nishino N, Yamauchi N, Ueno S, Konodoh K, Sano N, Takahashi M, Murayarna N, Kondo I, Nagafuchi S, Yamada M, Kanazawa I (1995) DNA analysis in hereditary dentatorubral‐pallidoluysian atrophy: Correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. Neurology 45: 143–149. [DOI] [PubMed] [Google Scholar]
91. Koroshetz WJ, Jankins BG, Rosen BR, Beal MF (1996) Energy metabolism defects in Huntington's disease and effects of coenzyme Q10. Ann Neurol 41: 160–165. [DOI] [PubMed] [Google Scholar]
92. Korsmeyer SJ (1995) Regulators of cell death. Trends Genet 11: 101–105. [DOI] [PubMed] [Google Scholar]
93. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN (1993) Bcl‐2/Bax: a rheostat that regulates an anti‐oxidant pathway and cell death. Semin Cancer Biol 4: 327–332. [PubMed] [Google Scholar]
94. Koshy B, Matilla T, Burright EN, Merry DE, Fischbeck KH, Orr HT, Zoghbi HY (1996) Spinocerebellar ataxia type‐1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde‐3‐phosphate dehydrogenase. Hum Mol Genet 5(9): 1311–1318. [DOI] [PubMed] [Google Scholar]
95. Koutouzis TK, Borlongan CV, Freeman TB, Cahill DW, Sanberg PR (1994) Intrastriatal 3‐nitropropionic acid: a behavioral assessment. Neuro Report 5(17): 2241–2245. [DOI] [PubMed] [Google Scholar]
96. Kowall NW, Ferrante RJ, Martin JB (1987) Patterns of cell loss in Huntington's disease. TINS 10: 24–29. [Google Scholar]
97. Kramer PL, Yue Q, Gancher ST, Nutt JG, Baloh R, Smith E, Browne D, Bussey K, Lovrien E, Nelson S, Litt M (1995) A locus for the nystagmus‐associated form of episodic ataxia maps to an 11‐cM region on chromosome 19p (letter to the editor). Am J Hum Genet 57: 182–185. [PMC free article] [PubMed] [Google Scholar]
98. Kuida K, Zheng TS, Na S, Kuan C‐y, Yang D, Karasuyama H, Rakic P, Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32‐deficient mice. Nature 384(6607): 368–372. [DOI] [PubMed] [Google Scholar]
99. La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa‐Petrusewicz I, Yee W‐C, Fischbeck KH (1992) Meiotic stability and genotype‐phenotype correlation of the trinucleotide repeat in X‐linked spinal and bulbar muscular atrophy. Nature Genet 2: 301–304. [DOI] [PubMed] [Google Scholar]
100. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fishbeck KH (1991) Androgen receptor gene mutations in X‐linked spinal and bulbar muscular atrophy. Nature 352: 77–79. [DOI] [PubMed] [Google Scholar]
101. Lange H, Thorner G, Hopf A, Schroder KF (1976) Morphometric studies of the neuropathological changes in choreatic diseases. J Neurol Sci 28: 401–425. [DOI] [PubMed] [Google Scholar]
102. Lanska DJ, Lanska MJ, Lavine L, Schoenberg BS (1988) Conditions associated with Huntington's disease at death. A case‐control study. Arch Neurol 45: 878–880. [DOI] [PubMed] [Google Scholar]
103. Legius E, Cuppens H, Dierick H, Van Zandt K, Dom R, Fryns J‐P, Evers‐Kiebooms G, Decruyenaere M, Demyttenaere K, Marynen P, Cassiman J‐J (1994) Limited expansion of the (CAG)n repeat of the Huntington gene: A premutation (?). Eur J Hum Genet 2: 44–50. [DOI] [PubMed] [Google Scholar]
104. Li X‐J, Li S‐H, Sharp AH, Nucifora FC Jr., Schilling G, Lanahan A, Worley P, Snyder SH, Ross CA (1995) A hunt‐ingtin‐associated protein enriched in brain with implications for pathology. Nature 378: 398–402. [DOI] [PubMed] [Google Scholar]
105. Li X‐J, Sharp AH, Li S‐H, Dawson TM, Snyder SH, Ross CA (1996) Huntingtin‐associated protein (HAP1): Discrete neuronal localization resemble those of neuronal nitric oxide synthase. Proc Natl Acad Sci USA 93: 4839–4844. [DOI] [PMC free article] [PubMed] [Google Scholar]
105b. Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell‐free extracts: requirement for dATP and cytochrome c. Cell 86(1): 147–157. [DOI] [PubMed] [Google Scholar]
106. Llinas R, Sugimori M, Hillman DE, Cherksey B (1992) Distribution and functional significance of the P‐type, voltage‐dependent Ca2+ channels in the mammalian central nervous system. TINS 15: 351–355. [DOI] [PubMed] [Google Scholar]
107. Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M (1991) 3‐nitropropionic acid‐ exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 18: 492–498. [DOI] [PubMed] [Google Scholar]
108. Ludolph AC, Seelig MO, Ludolph A, Novitt P, Allen CN, Spencer PS, Sabri MI (1992) 3‐Nitropropionic acid decreases cellular energy levels and causes neuronal degradation in cortical explants. Neurodegen 1: 21–28. [Google Scholar]
109. Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, Dawson DM, Sudarsky L, Guimaraes J, Loureiro JEL, Nezarati MM, Corwin LI, Lopes‐Cendes I, Rooke K, Rosenberg R, MacLeod P, Farrer LA, Sequeiros J, Rouleau GA (1995) Correlation between CAG repeat length and clinical features in Machado‐Joseph disease. Am J Hum Genet 57: 54–61. [PMC free article] [PubMed] [Google Scholar]
110. MacMillan JC, Snell RG, Tyler A, Houlihan GD, Fenton I, Cheadle JP, Lazarou LP, Shaw DJ, Harper PS (1993) Molecular analysis and clinical correlations of the Huntington's disease mutation. Lancet 342: 954–958. [DOI] [PubMed] [Google Scholar]
111. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD Gene with an Expanded CAG Repeat is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice. Cell 87: 493–506. [DOI] [PubMed] [Google Scholar]
112. Martin SJ, Finucane DM, Amarante‐Mendes GP, O'Brien GA, Green DR (1996) Phosphatidylserine externalization during CD95‐induced apoptosis of cells and cytoplasts requires ICE/CED‐3 protease activity. J Biol Chem 271(46): 28753–28756. [DOI] [PubMed] [Google Scholar]
113. Martin SJ, Green DR (1995) Protease Activation during Apoptosis: Death by a Thousand Cuts Cell 82: 349–352. [DOI] [PubMed] [Google Scholar]
113b. Martin SJ, Newmeyern DD, Mathias S, Farschon DM, Wang HG, Reed JC, Kolesnick RN, Green DR (1995) Cell‐free reconstitution of Fas‐, UV radiation‐ and ceramide‐induced apoptosis. EMBO Journal 14(21): 5191–5200. [DOI] [PMC free article] [PubMed] [Google Scholar]
114. Maruyama H, Nakamura S, Matsuyama Z, Sakai T, Doyu M, Sobue G, Seto M, Tsujihata M, Oh‐i T, Nishio T, Sunohara N, Takahaski R, Hayashi M, Nishino I, Ohtake T, Oda T, Nishimura M, Saida T, Matsumoto H, Baba M, Kawaguchi Y, Kakizuka A, Kawakami H (1995) Molecular features of the CAG repeats and clinical manifestation of Machado‐Joseph disease. Hum Mol Genet 4(5): 807–812. [DOI] [PubMed] [Google Scholar]
115. Matsuishi T, Sakai T, Naito E, et al (1996) Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado‐Joseph disease. Acta Neurol Scand 93: 72–75. [DOI] [PubMed] [Google Scholar]
116. Mecicci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC, Beal MF (1993) Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain. Ann Neurol 34: 609–616. [DOI] [PubMed] [Google Scholar]
117. Mejean C, Pons F, Benyamin Y, Roustan C (1989) Antigenic prebes locate binding sites for the glycolutic enzymes glyceraldehyde‐3‐phosphate dehydrogenase, aldolase and phosphofructokinase on the actin monomer in microfilaments. Biochem J 264: 671–677. [DOI] [PMC free article] [PubMed] [Google Scholar]
118. Menzies RA, Gold PH (1971) The turnover of mitochondria in a variety of tissues of young adult and aged rats. J Biol Chem 246: 2425–2429. [PubMed] [Google Scholar]
119. Meyer‐Siegler K, Mauro DJ, Seal G, Wurzer J, DeRiel JK, Sirover MA (1991) A human nuclear uracil DNA glycosylase is the 37‐kDa subunit of glyceraldehyde‐3‐phosphate dehydrogenase. Proc Natl Acad Sci USA 88: 8460–8464. [DOI] [PMC free article] [PubMed] [Google Scholar]
120. Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M, Thompson CB (1997) Bcl‐xL forms an ion channel in synthetic lipid membranes. Nature 385: 353–357. [DOI] [PubMed] [Google Scholar]
121. Mori Y, Friedrich T, Kim M‐S, Mikami A, Nakai J, Ruth P, Bosse E, Hofmann F, Flockerzi V, Furiuchi T, Mikoshiba K, Imoto K, Tanabe T, Numa S (1991) Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350: 398–402. [DOI] [PubMed] [Google Scholar]
122. Munday NA, Vaillancourt JP, Ali A, Casano FJ, Miller DK, Molineaux SM, Yamin T‐T, Yu VL, Nicholson DW (1995) Molecular cloning and pro‐apoptotic activity of ICEreIII and ICEreIII, members of the ICE/CED‐3 family of cysteine proteases. J Biol Chem 270(26): 15870–15876. [DOI] [PubMed] [Google Scholar]
123. Munn AL. Stevenson BJ, Geli MI, Reizman H (1996) end5, end6, and end7: Mutations that cause actin derealization and block the internalization step of endocyto‐sis in Saccharomyces cerevisiae. Mol Biol Cell 6: 1721–1742. [DOI] [PMC free article] [PubMed] [Google Scholar]
124. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko NJ, Scaffidi C, Bretz JD, Zhang M, Gentz R, et al. (1996) Flice, a novel FADD‐homologous ICE/CED‐3 like protease, is recruited to the CD95 (Fas/APO‐1) death‐inducing signaling complex. Cell 85: 817–827. [DOI] [PubMed] [Google Scholar]
125. Myers RH, Leavitt J, Karner LA, Farrer L, Jagedeesh J, McFarlane H, Mastromouro CA, Mark RJ, Gusella JF (1989) Homozygore for Huntington disease. Am J Hum Genet 45: 615–618. [PMC free article] [PubMed] [Google Scholar]
126. Na S, Hincapie M, McCusker JH, Haber JE (1995) MOP2 (SLA2) affects the abundance of the plasma membrane H+‐ATPase of Saccharomyces cerevisiae. J Biol Chem 270(12): 6815–6823. [DOI] [PubMed] [Google Scholar]
127. Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, Tanaka Y, Kirushima H, Umino K, Kurosawa H, Furukawa T, Hikei K, Inoue T, Sano A, Komure O, Takahashi M, Yoshizawa T, Kanazawa I, Yamada M (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nature Genet 6: 14–18. [DOI] [PubMed] [Google Scholar]
128. Nagy E, Rigby WF (1995) Glyceraldehyde‐e‐phosphate dehydrogenase selectively binds AU‐rich RNA in the NAD(+)‐binding region (Rossmann fold). J Biol Chem 270: 2755–2763. [DOI] [PubMed] [Google Scholar]
129. Nance MA (1996) Huntington disease ‐ another chapter rewritten. Editorial review. Am J Hum Genet 59(1): 1–6. [PMC free article] [PubMed] [Google Scholar]
130. Nasir J, Goldberg YP, Hayden MR (1996) Huntington disease: new insights into the relationship between CAG expansion and disease. Invited Review, Hum Mol Genet 5: 1431–1435. [DOI] [PubMed] [Google Scholar]
131. Nasir S, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borouski A, Marth JD, Phillips AG, Hayden MR (1995) Targeted disruption of the murine Huntington disease gene results in early post‐implantation embryonic lethality and behavioral and morphological abnormalities in heterozygotes. Cell 81: 811–823. [DOI] [PubMed] [Google Scholar]
131b. Newmeyer DD, Farschon DM, Reed JC (1994) Cell‐free apoptosis in Xeniopus egg extracts: inhibition by Bcl‐2 and requirement for an organelle fraction enriched in mitochondria. Cell 79: 353–364. [DOI] [PubMed] [Google Scholar]
132. Nicholson DW (1996) ICE/CED3‐like proteases as therapeutic targets for the control of inappropriate apoptosis. Nature Biotech 14: 297–301. [DOI] [PubMed] [Google Scholar]
133. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson ME, Yamin T‐T, Yu VL, Miller DK (1995) Identification and inhibition of the ICE/CED‐3 protease necessary for mammalian apoptosis. Nature 376: 37–43. [DOI] [PubMed] [Google Scholar]
134. Norremolle A, Riess O, Epplen JT, Fenger K, Hasholt L, Sorenson SA (1993) Trinucleotide repeat elongation in the Huntington gene in Huntington disease patients from 71 Danish families. Hum Mol Genet 2: 1475–1476. [DOI] [PubMed] [Google Scholar]
135. Novelletto A, Persichetti F, Sabbadini G, Mandich P, Bellone E, Ajmar F, Pergola M, Dei Sanno L., MacDonald ME, Gusella JF, Frcntali M (1994) Analysis of the trinucleotide repeat expansion in Italian families affected with Huntington disease. Hum Mol Genet 3(1): 93–98. [DOI] [PubMed] [Google Scholar]
136. Onodera O, Roses AD, Tsuji S, Vance JM, Strittmatter WJ, Burke JR (399) Toxicity of expanded polyglutamine‐domain proteins in Escherichia coli. FEBS Letters 135: 139. [DOI] [PubMed] [Google Scholar]
137. Palfi S, Ferrante RJ, Brouillet E, Beal MF, Dolan R, Guyot MC, Peschanski M, Hantraye P (1996) Chronic 3‐nitro‐propionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington's disease. J Neuro 16(9): 3019–3025. [DOI] [PMC free article] [PubMed] [Google Scholar]
138. Parker, W. D. , Boyson SJ, Luder AS, Parks JK (1990) Evidence for a defect in NADH: uibiquinone oxidoreduc‐tase (complex I) in Huntington's disease. Neurology 40: 1231–1234. [DOI] [PubMed] [Google Scholar]
139. Perutz MF, Johnson T, Suzuki M, Finch JT (1994) Glutamine repeats as polar zippers: their possible rele in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 91: 5355–5358. [DOI] [PMC free article] [PubMed] [Google Scholar]
140. Petit PX, Susin S‐A, Zamzami N, Mignotte B, Kroemer G (1996) Mitochondria and programmed cell death: back to the future. FEBS Letters 396: 7–13. [DOI] [PubMed] [Google Scholar]
141. Protera‐Cailliau C, Hedreer, JC , Price DL, Koliatsos VE (1995) evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci 15(5): 3775–3787. [DOI] [PMC free article] [PubMed] [Google Scholar]
142. Ranum LPW, Chung M‐y, Banfi S, Bryer A, Schut LJ, Ramesar R, Duvick LA, McCall AE, Subramcny SH, Goldfarb L, Gomez C, Sandkuijl LA, Orr HT, Zoghbi HY (1994) Molecular and clinical correlations in spinocerebellar ataxia type 1 (SCA1): evidence for familial effects on the age of onset. Am J Hum Genet 55: 244–252. [PMC free article] [PubMed] [Google Scholar]
143. Reed JC (1994) Bcl‐2 and the regulation of programmed cell death (Review). J Cell Biol 124(1–2): 1–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
144. Richardson EP Jr. (1990) Huntington's disease: some recent neuropathological studies. Neuropathol Appl Neurobiol 16: 451–460. [DOI] [PubMed] [Google Scholar]
145. Richfield EK, Maguire‐Zeiss KA, Vonkeman HE, Voorn P (1995) Preferential loss of preproenkephalin versus pre‐ protakykinin neurons from the striatum of Huntington's disease patients. Ann Neurol 38: 852–861. [DOI] [PubMed] [Google Scholar]
146. Ronai Z (1993) Glycolytic enzymes as DNA binding proteins. Int J Biochem 25: 1073–1076. [DOI] [PubMed] [Google Scholar]
147. Ross CA (1995) When more is less: Pathogenesis of glu‐tamine repeat neurodegenerative diseases. Neuron 15: 493–496. [DOI] [PubMed] [Google Scholar]
148. Rubinsztein DC, Barton DE, Davison BCC, Ferguson‐Smith MA (1993) Analysis of the huntingtin gene reveals a trinucleotide‐length polymorphism in the region of the gene that contains two CCG‐rich stretches and a correlation between decreased age of onset of Huntington's disease and CAG repeat number. Hum Mol Genet 2: 1713–1715. [DOI] [PubMed] [Google Scholar]
149. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman J‐J, Chotai K, Connarty M, Craufurd D, Curtis A, Curtis D, Davidson MJ, Differ A‐M, Dode C, Dodge A, Frontali M, Ranen MG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Jackson A, Kaplan J‐C, Losekoot M, MacMillan JC, Morrison P, Trottier Y, Novelletto A, Simpson SA, Theilmann J, Whittaker JL, Folstein SE, Ross CA, Hayden MR (1996) Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington's disease gene (HD) reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am J Hum Genet 59: 16–22. [PMC free article] [PubMed] [Google Scholar]
150. Schiffer D, Attanasino A, Chio A, Migheli A, Pezzulo T (1994) Ubiquitinated dystrophic neurites suggest corticospinal derangement in patients with amyotrophic lateral sclerosis. Neuro Lett 180: 21–24. [DOI] [PubMed] [Google Scholar]
151. Schulz JB, Matthews RT, Jenkins BG, Ferrante R. J., Siewk D, Henshaw DR, Cipolloni PB, Mecocci P, Kowall NW, Rosen BR, Beal MF (1995) Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neuro 15(12): 8419–8429. [DOI] [PMC free article] [PubMed] [Google Scholar]
152. Schulze H, Schuler A, Stüber, Dobeli H, Langen H, Huber G (1993) Rat Brain Glyceraldehyde‐3‐Phosphate Dehydrogenase Interacts with the Recombinant Cytoplasmic Domain of Alzheimer's beta‐Amyloid Precursor Protein. J Neurochem 60(5): 1915–1992. [DOI] [PubMed] [Google Scholar]
153. Servadio A, Koshy B, Armstrong D, Antalffy B, Orr HT, Zoghbi HY (1995) Expression analysis of the ataxin‐1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genef 10(1): 94–98. [DOI] [PubMed] [Google Scholar]
154. Shimizu S, Eguchi Y, Kamiike W, Waguri S, Uchiyama YI, Matsuda H, Tsujimoto Y (1996) Bcl‐2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. Oncogene 13: 21–29. [PubMed] [Google Scholar]
155. Sigiyama H, Hainfeller JA, Yoshimura M, Budka H (1994) Neocortical changes in Parkinson's disease, revisited. Clin Neuropath 13: 55–59. [PubMed] [Google Scholar]
156. Simpson SA, Davidson MJ, Barron LH (1993) Huntington's disease in Grampian region: correlation of the CAG repeat number and the age of onset of the disease. J Med Genet 30(12): 1014–1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
157. Singh R, Green MR (1993) Sequence specific binding of transfer RNA by glyceraldehyde‐3‐phosphate dehydrogenases. Science 259: 365–368. [DOI] [PubMed] [Google Scholar]
158. Skulachev VP (1996) Why are mitochondria involved in apoptosis FEBS Letters 387: 7–10. [DOI] [PubMed] [Google Scholar]
159. Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P, MacDonaid ME, Gusella JF, Harper PS, Shaw DJ (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nature Genet 4(4): 393–397. [DOI] [PubMed] [Google Scholar]
160. Somers M, Engelborghs Y, Baert J (1990) Analysis of the binding of glyceraldehyde‐3‐phosphate dehydrogenase to microtubules, the mechanism of bundle formation and the linkage effect. Eur J Biochem 193: 437–444. [DOI] [PubMed] [Google Scholar]
161. Song Q, Wei T, Lees‐Miller S, Alnemri E, Watters D, Lavin MF (1997) Resistance of actin to cleavage during apoptosis. Proc Natl Acad Sci USA 94(1): 157–162. [DOI] [PMC free article] [PubMed] [Google Scholar]
162. Soong B‐W, Wang JT (1995) A comparison of the Huntington's disease associated trinucleotide repeat between Chinese and white populations. J Med Genet 32: 404–408. [DOI] [PMC free article] [PubMed] [Google Scholar]
163. Soong N‐W, Hinton DR, Cortpassi G, Arnheim N (1992) Mosaicism for a specific mitochondrial DNA mutation in adult human brain. Nature Genet 2: 318–323. [DOI] [PubMed] [Google Scholar]
164. Srinivasula SM, Fernandes‐Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (1996) The Ced‐3/Interleukin 1beta converting enzyme‐like homolog Mch6 and the lamin‐cleaving enzyme Mch2 alpha are substrates for tne apoptotic mediator CPP32. J Biol Chem 271(43): 27099–27106. [DOI] [PubMed] [Google Scholar]
165. Stine OC, Pleasant N, Franz ML, Abbott MH, Folstein SE, Ross CA (1993) Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT‐15 Hum Mol Genef 2(10): 1547–1549. [DOI] [PubMed] [Google Scholar]
166. Taddei N, Liguri G, Sorbi S, Amaducci L, Camici G, Cecchi C, Ramponi G (1993) Cerebral soluble ubiquitin is increased in patients with Alzheimer's disease. Neuro Lett 151: 158–161. [DOI] [PubMed] [Google Scholar]
167. Takai D, Inoue K, Shisa H, Kagawa Y, Hayashi JI (1995) Age‐associated changes of mitochondrial translation and respiratory function in mouse brain. Biochem & Biophys Res Comm 217: 668–674. [DOI] [PubMed] [Google Scholar]
168. Takiyama Y, Igarashi S, Rogaeva EA, Endo K, Rogaev EI, Tanaka H, Sherrington R, Sanpei K, Liang Y, Saito M, Tsuda T, Takano H, Ikeda M, Lin C, Chi H, Kennedy JL, Lang AE, Wherrett JR, Segawa M, Nomura Y, Yuasa T, Weissenbach J, Yoshida M, Nishizawa M, Kidd KK, Tsuji S, St George‐Hyslop PH (1995) Evidence for inter‐generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado‐Joseph disease. Hum Mol Genet 4(7): 1137–1146. [DOI] [PubMed] [Google Scholar]
169. Tellez‐Nagel I, Johnson AB, Terry RD (1973) Ultrastructural and histochemical study of cerebral biopsies in Huntington's chorea. Adv Neurol 1: 387–397. [Google Scholar]
170. Tewari M, Quc. n LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirer GG, Salvesen GS, Dixit VM (1995) Yama/CPP32beta, a Mammalian Homolog of CED‐3, Is a CrmA‐lnhibitable Protease That Cleaves the Death Substrate Poly(ADP‐Ribose) Polymerase. Cell 81: 801–809. [DOI] [PubMed] [Google Scholar]
171. Thomas LB, Gates DJ, Richfield EK, O'Brien TF, Schweitzer JB, Steindler DA (1995) DNA End Labeling (TUNEL) in Huntington's Disease and Other Neuropathological Conditions. Exp Neurol 133: 265–272. [DOI] [PubMed] [Google Scholar]
172. Trottier Y, Biancalana V, Mandel JL (1994) Instability of CAG repeats in Huntington's disease: relationship to parental transmission and age of onset. J Med Genet 31(5): 377–382. [DOI] [PMC free article] [PubMed] [Google Scholar]
173. Vahedi K, Joutel A, Van Bogaert P, Ducros A, Maciazeck J, Bach JF, Bousser MG, Toumier‐Lasserve E (1995) A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 37(3): 289–293. [DOI] [PubMed] [Google Scholar]
174. Vincenz C, Dixit VM (1997) Fas‐associated death domain protein interleukin‐1 beta‐converting enzyme 2 (FLICE2), an ICE/CED‐3 homologue, is proximally involved in CD95‐ and p55‐mediated death signaling. J Biol Chem 272(10): 6578–6583. [DOI] [PubMed] [Google Scholar]
175. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. (1985) Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 44: 559–577. [DOI] [PubMed] [Google Scholar]
176. Wallace DC (1992) Mitochondrial Genetics: A paradigm for aging and degenerative diseases Science 256: 628–632. [DOI] [PubMed] [Google Scholar]
177. Wang L, Miura M, Bergeron L, Zhu H, Yuan J (1994) Ich‐1, an Ice/ced‐3‐related gene, encodes both positive and negative regulators of programmed cell death. Cell 78: 739–750. [DOI] [PubMed] [Google Scholar]
178. Wang X, Zelenski NG, Yang J, Sakai J, Brown MS, Goldstein JL (1996) Cleavage of sterol regulatory element binding proteins (SREBPs) by CPP32 during apoptosis. Embo J 15: 1012–1020. [PMC free article] [PubMed] [Google Scholar]
179. Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, Tait D, Colicelli J, Lehrach H (1997) HIP1: A huntingtin interacting protein isolated by the yeast two‐hybrid system. Hum Mol Genet 6: 487–495. [DOI] [PubMed] [Google Scholar]
180. Wexler NS, Young AB, Tanzi RE, Travers H, Starosta‐Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA (1987) Homozygotes for Huntington's disease. Nature 326: 194–197. [DOI] [PubMed] [Google Scholar]
181. Wong‐Riley MTT (1989) Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. TINS 12(3): 94–101. [DOI] [PubMed] [Google Scholar]
182. Wu D, Wallen HD, Nunez G (1997) Interaction and regulation of subcellular localization of CED‐4 by CED‐9. Science 275: 1126–1129. [DOI] [PubMed] [Google Scholar]
183. Yang E, Korsmeyer SJ (1996) Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 88(2): 386–401. [PubMed] [Google Scholar]
183b. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T‐I, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl‐2: Release of cytochrome c from mitochondria blocked. Science 275: 1129–1132. [DOI] [PubMed] [Google Scholar]
184. Yuan J‐Y, Shaham S, Ledoux S, Ellis HJM, Horvitz HR (1993) The C. elegans cell death gene ced‐3 encodes a protein similar to mammalian interleukin‐1 beta‐converting enzyme. Cell 75: 641–652. [DOI] [PubMed] [Google Scholar]
185. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroerer G (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182: 367–377. [DOI] [PMC free article] [PubMed] [Google Scholar]
186. Zeitlin S, Liu J‐P, Chapman DL, Papaioannou VE. Efstratiadis A (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature Genet 11: 155–162. [DOI] [PubMed] [Google Scholar]
187. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amox D, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alphalA‐voltage‐dependent calcium channel. Nature Genet 15: 62–69. [DOI] [PubMed] [Google Scholar]
188. Zuhlke C, Riess O, Shroder K, Siedlaczck I, Epplen JT, Engel W, Thies U (1993) Expansion of the (CAG)n repeat causing Huntington's disease in 352 patients of German origin. Hum Mol Genet 2: 1467–1469. [DOI] [PubMed] [Google Scholar]

[b1] 1. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12: 366–375. [DOI] [PubMed] [Google Scholar]

[b2] 2. Andrade MA, Bork P (1995) HEAT repeats in the Huntington's disease protein. Nature Genet 11: 115–116. [DOI] [PubMed] [Google Scholar]

[b3] 3. Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA, Graham RK, Hayden MR (1993) The relationship between trinucleotide repeat (CAG) length and clinical features of Huntington disease. Nature Genet 4: 398–403. [DOI] [PubMed] [Google Scholar]

[b4] 4. Banfi S, Servadio A, Chung M‐y, Kwiatkowski TJ Jr., McCall AE, Duvick LA, Shen Y, Roth EJ, Orr HT, Zoghbi HY (1994) Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nature Genet 7: 513–519. [DOI] [PubMed] [Google Scholar]

[b5] 5. Barron L, Warner J, Porteous M, Holloway S, Simpson S, Davidson R, Brock DJH (1993) A study of the Huntington's disease associated trinucleotide repeat in the Scottish population. J Med Genet 30(12): 1003–1007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b6] 6. Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses Ann Neurol 31: 119–130. [DOI] [PubMed] [Google Scholar]

[b7] 7. Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38: 357–366. [DOI] [PubMed] [Google Scholar]

[b8] 8. Beal MF, Brouillet E, Jenkins BG, Ferrante FJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993) Neurochemical and histologic characterization of striatal excilotoxic lesions produced by the mitochondrial toxin 3‐nitroproprionic acid. J Neuro 13(10): 4181–4192. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b9] 9. Beal MF, Ferrante RJ, Swartz KJ, Kowall NW (1991) Chronic quinclinic acid lesions in rats closely resemble Huntington's cisease. J Neurosci 11: 1649–1659. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b10] 10. Beal MF, Hyman BT, Koroshetz W (1993) Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases TINS 17(3): 107–108. [DOI] [PubMed] [Google Scholar]

[b11] 11. Beal MF, Lowall NW, Swartz KJ, Ferrante RJ, Martin JB (1989) Differential sparing of somatostatin‐neuropeptide Y and cholinergic neurons following striatal excitotoxin lesions. Synapse 3: 38–47. [DOI] [PubMed] [Google Scholar]

[b12] 12. Behrens MI, Koh J, Canzoniero LMT, Sensi SL, Csemansky CA, Choi DW (1995) 3‐Nitroproprionic acid induces apoptosis in cultured striatal and cortical neurons. Neuro Report 6(3): 545–548. [DOI] [PubMed] [Google Scholar]

[b13] 13. Benitez J, Fernandez E, Garcia Ruiz P, Robledo M, Ramos C, Yebenes J (1994) Trinucleotide (CAG) repeat expansion in chromosomes of Spanish patients with Huntington's disease. Hum Genet 94: 563–564. [DOI] [PubMed] [Google Scholar]

[b14] 14. Boldin MP, Goncharov TM, Golstev YV, Wallach D (1996) Involvement of MACH, a novel MORT/FADD‐interacting protease, in Fas/Apo‐1‐ and TNF receptor‐induced cell death. Cell 85: 803–815. [DOI] [PubMed] [Google Scholar]

[b15] 15. Borlongan CV, Koutouzis TK, Freeman TB, Cahill DW, Sanberg PR (1995) Behavioral pathology induced by repeated systemic injections of 3‐nitropropionic acid mimics the motoric symptoms of Huntington's disease. Brain Research 697: 254–257. [DOI] [PubMed] [Google Scholar]

[b16] 16. Borlongan CV, Koutouzis TK, Randall TS, Freeman TB, Cahill DW, Sandberg PR (1995) Systemic 3‐nitropropionic acid: behavioral deficits and striatal damage in adult rats. Brain Research Bulletin 36(6): 549–556. [DOI] [PubMed] [Google Scholar]

[b17] 17. Bowling AC, Mutisya EM, Walker LC, Price DL, Cork LC, Beal MF (1993) Age‐dependent impairment of mitochondrial function in primate brain. J Neurochem 60: 1964–1967. [DOI] [PubMed] [Google Scholar]

[b18] 18. Brancolini C, Benedetti M, Schneider C (1995) Microfilament reorganization during apoptosis: the role of Gas2, a possible substrate for ICE‐like proteases. EMBO Journal 14: 5179–5190. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b19] 19. Brinkman RR, Mezei MM, Thielmann J, Almqvist E, Hayden MR (1997) The likelihood of being affected with Huntington disease by a particular age for a specific CAG size. Am J Hum Genet 60: 1202–1210. [PMC free article] [PubMed] [Google Scholar]

[b20] 20. Brouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy‐Willig A, Kowall NW, Beal MF (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Prcc Natl Acad Sci USA 92: 7105–7109. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b21] 21. Brouillet E, Jenkins BG, Hyman BT, Ferrante RJ, Kowall NW, Srivastava R, Roy DS, Rosen BR, Beal MF (1993) Age‐dependent vulnerability of the striatum to the mitochondrial toxin 3‐nitropropionic acid. J Neurochem 60: 356–359. [DOI] [PubMed] [Google Scholar]

[b22] 22. Burke JR, Enghild JJ, Margin ME, Joy Y‐S, Myers RM, Roses AD, Vance JM, Strittmatter WJ (1996) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Genet 2(3): 347–350. [DOI] [PubMed] [Google Scholar]

[b23] 23. Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HT (1995) SCA1 Transgenic Mice: A Model for Neurodegeneration Caused by an Expanded CAG Trinucleotide Repeat. Cell 82: 937–948. [DOI] [PubMed] [Google Scholar]

[b24] 24. Cammarata S, Caponnetto C, Tabaton M (1993) Ubiquitin‐reactive neurites in cerebral cortex of subjects with Huntington's chorea: a pathological correlate of dementia Neuro Lett 156: 96–98. [DOI] [PubMed] [Google Scholar]

[b25] 25. Casciola‐Rosen LA, Grant JA, Rosen A (1995) DNA‐dependent protein kinase is one of a subset of autoanti‐gens specifically cleaved early during apoptosis. J Exp Med 182: 1625–1634. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b26] 26. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Ness KV, Greenstreet TA, March CJ, Krorheim SR, Druck T Cannizzaro LA, Huebner K, Black RA (1992) Molecular cloning of the interlenkin‐1β converting enzyme. Science 256: 97–100. [DOI] [PubMed] [Google Scholar]

[b27] 27. Chen Z, Niles EG, Pickart CM (1991) Isolation of a cDNA encoding a mammalian multiubiquitinating enzyme (E225K) and overexpression of the functional enzyme in Escherichia coli. J Biol Chem 266: 15698–15704. [PubMed] [Google Scholar]

[b28] 28. Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM (1997) Interaction of CED‐4 with CED‐3 and CED‐9: A molecular framework for cell death. Science 275: 1122–1126. [DOI] [PubMed] [Google Scholar]

[b29] 29. Claes S, Van Zand K, Legius E, Dom R, Malfroid M, Baro F, Godderis J, Cassiman J‐J (1995) Correlations between triplet repeat expansion and clinical features in Huntington's disease. Archives of Neurology 52: 749–753. [DOI] [PubMed] [Google Scholar]

[b30] 30. Coles CJ, Edmonson DE, Singer TP (1979) Inactivation of succinate dehydrogenase by 3‐nitropropionate. J Biol Chem 254(12): 5141–5167. [PubMed] [Google Scholar]

[b31] 31. Corral‐Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC (1992) Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet 2: 324–329. [DOI] [PubMed] [Google Scholar]

[b32] 32. Cortopassi GA, Shibata D, Soong N‐W, Arnheim N (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 89: 7370–7374. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b33] 32b. Cosulich SC, Green S, Clarke PR (1996) Bcl‐2 regulates activation of apoptotic proteases in a cell‐free system. Curr Biol 6(8): 997–1005. [DOI] [PubMed] [Google Scholar]

[b34] 33. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative diseases. Ann Neurol 38: 357–366. [DOI] [PubMed] [Google Scholar]

[b35] 34. Crauford D, Dodge A (1993) Mutation size and age at onset in Huntington's disease. J Med Genet 30: 1008–1011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b36] 35. Cryns VL, Bergeron L, Zhu H, Li H, Yuan J (1996) Specific cleavage of alpha‐fodrin during Fas‐ and tumor necrosis factor‐induced apoptosis is mediated by an interleukin‐beta‐converting enzyme/CED‐3 protease distinct from the poly(ADP‐ribose)polymerase protease. J Biol Chem 271(49): 31277–31282. [DOI] [PubMed] [Google Scholar]

[b37] 36. Dawburn D, De Quidt ME, Emson PC (1985) Survival of basal ganglia neuropeptide Y‐somatostatin neurones in Huntington's disease. Brain Res 340: 251–260. [DOI] [PubMed] [Google Scholar]

[b38] 37. Dawson VL, Kizushi VM, Huang PL, Snyder SH, Dawson TM (1996) Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase ‐ deficient mice. J Neuro 16(8): 2479–2487. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b39] 38. de Grey ADNJ (1997) A proposed refinement of the mitochondrial free radical theory of aging. BioEssays 19: 161–167. [DOI] [PubMed] [Google Scholar]

[b40] 39. De Rooij KE, De Koning Gans PA, Skraastad MI, Belfroid RD, Vegter‐van der Vlis M, Roos RA, Bakker E, van Ommen GJ, Den Dunnen JT, Losekoot M (1993) Dynamic mutation in Dutch Huntington's disease patients: increased paternal repeat instabilities extending to within the normal size range. J Med Genet 30(12): 996–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b41] 40. Deshaies RJ (1995) Make it or break it: the role of ubiquitin‐dependent proteolysis in cellular regulation. Trends Cell Biol 5: 428–434. [DOI] [PubMed] [Google Scholar]

[b42] 41. Dragunow M, Faull RLM, Lawlor P, Beihartz EJ, Singleton K, Walker EB, Mee E (1995) In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Clin Neurosci Neuropath 6: 1053–1057. [DOI] [PubMed] [Google Scholar]

[b43] 41b. Duan H, Chinnaiyan AM, Hudson PC, Wing JP, He WW, Dixit VM (1996) ICE‐LAP3, a novel mammalian homo‐logue of the caenorhaloditis elegans cell death protein CED‐3 is activated during Fas‐ and Tumor necrosis factor‐induced apoptosis. J Biol Chem 271: 1621–1625. [DOI] [PubMed] [Google Scholar]

[b44] 43. Duan H, Orth K, Chinnaiyan AM, Poirier GG, Froelich CJ, He W‐W, Dixit VM (1996) ICE‐LAP6, a novel member of the ICE‐CED‐3 gene family, is activated by the cytotoxic T cell protease granzyme B‐. J Biol Chem 271(28): 16720–16724. [DOI] [PubMed] [Google Scholar]

[b45] 44. Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M, Gray J, Conneally P, Young A, Penney J, Hollingsworth Z, Shoulson I, Lazzarini A, Falek A, Koroshetz W, Sax D, Bird E, Vonsattel J, Bonilla E, Alvir J, Bickham Conde J, Cha J‐H, Dure L, Gomez F, Ramos M, Sanchez‐Ramos J, Snodgrass S, de Young M, Wexler N, Moscowitz C, Penchaszadeh G, MacFarlane H, Anderson M, Jenkins B, Srinidhi J, Barnes G, Gusella J, MacDonald M (1993) Trinucleotide repeat length instability in Huntington disease. Nature Genet 4: 387–392. [DOI] [PubMed] [Google Scholar]

[b46] 45. Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, Ge P, Vonsattel J‐P, Gusella JF, Joyner AL, MacDonald ME (1995) Inactivation of the Mouse Huntington's Disease Gene Homolog Hdh. Science 269: 407–410. [DOI] [PubMed] [Google Scholar]

[b47] 46. Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cell 44: 817–829. [DOI] [PubMed] [Google Scholar]

[b48] 47. Erecinska M, Dagani F (1990) Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes. J Gen Physiol 95(4): 591–616. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b49] 48. Erecinska M, Nelson D (1994) Effects of 3‐nitropropionic acid on synaptosomal energy and transmitter metabolism: relevance to neurodegenerative brain diseases. J Neurochem 63(3): 1033–1041. [DOI] [PubMed] [Google Scholar]

[b50] 49. Farrow SN, Brown R (1996) New members of the Bcl‐2 family and their protein partners. Curr Opin Genet Devel 6: 45–49. [DOI] [PubMed] [Google Scholar]

[b51] 50. Faucheu C, Blanchet AM, Collard‐Dutilleul V, Lalanne JL, Diu‐Hercend A (1996) Identification of a cysteine protease closely related to interieukin‐1 beta‐converting enzyme. Eur J Biochem 236(1): 207–213. [DOI] [PubMed] [Google Scholar]

[b52] 51. Faucheu C, Diu A, Chang AWE, Blanchet A‐M, Miossec C, Hervé F, Collard‐Dutilieul V, Gu Y, Aldape RA, Lippke JA, Rocher C, Su MS‐S, Livingston DJ, Hercend T, Lalanne J‐L (1995) A novel human protease similar to the interleukin‐1beta converting enzyme induces apoptosis in transfected cells. EMBO Journal 14(9): 1914–1922. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b53] 52. Fernandes‐Alnemri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (1996) In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD‐like domains. Proc Natl Acad Sci USA 93: 7464–7469. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b54] 54. Fernandes‐Alremri T, Litwack G, Alnemri ES (1994) CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein CED‐3 and mammalian interleukin‐1 beta converting enzyme. J Biol Chem 270: 30761–30764. [PubMed] [Google Scholar]

[b55] 55. Fernandes‐Alnemri T, Takahashi A, Armstrong R, Krebs J, Fritz L, Tomaselli KJ, Wang L, Yu Z, Croce CM, Salveson G, Earnshaw WC, Litwack G, Alnemri ES (1995) Mch3, A novel human E. poptotic cysteine protease highly related to CPP32. Cancer Research 55(24): 6045–6052. [PubMed] [Google Scholar]

[b56] 56. Ferrante RJ, Kowall NW, Beal MF, Richardson EP, Jr. , Bird ED, Martin JB (1985) Selective sparing of a class of striatal neurons in Huntington's disease. Science 230: 561–563. [DOI] [PubMed] [Google Scholar]

[b57] 57. Fletcher CF, Lutz CM, O'Sullivan TN, Shaughnessy JD Jr., Hawkes R, Frankel WN, Copeland NG, Jenkins NA (1996) Absence epilepsy in Tottering mutant mice is associated with calcium channel defects. Cell 87: 607–617. [DOI] [PubMed] [Google Scholar]

[b58] 58. Fox JB, Dandliker WB (1956) A study of some of the physical properties of glyceraldehyde‐3‐phosphate dehydrogenase. J Biol Chem 218: 53–57. [PubMed] [Google Scholar]

[b59] 59. Freese A, DiFiglia M, Koroshetz M, Beal MF, Martin JB (1990) Characterization and mechanism of glutamate neurotoxicity in primary striatal cultures. Brain Research 521:254–264. [DOI] [PubMed] [Google Scholar]

[b60] 60. Goldberg YP, Andrew SE, Clarke LA, Hayden MR (1993) A PCR methcd for accurate assessment of trinucleotide repeat expansion in Huntington disease. Hum Mol Genet 2(6): 635–636. [DOI] [PubMed] [Google Scholar]

[b61] 61. Goldberg YP, Kalchman MA, Metzler M, Nasir J, Zeisler J, Graham R, Koide HB, O'Kusky J, Sharp AH, Ross CA, Jirik F, Hayden MR (1996) Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript. Hum Mol Genet 5(2): 177–185. [DOI] [PubMed] [Google Scholar]

[b62] 62. Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Gromm M, Kazemi‐Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR (1996) Cleavage of nuntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet 13: 442–449. [DOI] [PubMed] [Google Scholar]

[b63] 63. Gould DH, Gustine DL (1982) Basal ganglia degeneration, myelin alterations, and enzyme inhibition induced in mice by the plant toxin 3‐nitropropionic acid. Neuropathol Appl Neurobiol 8: 377–393. [DOI] [PubMed] [Google Scholar]

[b64] 64. Gould DH, Wilson MP, Hamar DW (1985) Brain enzyme and clinical alterations induced in rats and mice by nitroaliphatic toxicants. Toxicol Lett 27: 83–89. [DOI] [PubMed] [Google Scholar]

[b65] 65. Graveland GA, Williams RS, DiFiglia M (1985) A golgi study of the human neostriatum: neurons and afferent fibers. J Comp Neurol 234: 317–333. [DOI] [PubMed] [Google Scholar]

[b66] 66. Greidinger EL, Miller DK, Yamin TT, Casciola‐Rosen L, Rosen A (1996) Sequential activation of three distinct ICE‐like activities in Fas‐ligated Jurkat cells. FEBS Letters 390(3): 299–303. [DOI] [PubMed] [Google Scholar]

[b67] 67. Gross NJ, Getz GS, Rabinowitz M (1969) Apparent turnover of mitochondrial deoxyribonucleic acid and mitochondrial phospholipids in the tissues of the rat. J Biol Chem 244: 1552–1562. [PubMed] [Google Scholar]

[b68] 68. Gu M, Gash MT, Mann VM, Javoy‐Agid F, Cooper JM, Schapira HV (1996) Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 39: 172–177. [DOI] [PubMed] [Google Scholar]

[b69] 69. Hacker G, Vaux DL (1995) A sticky business. Curr Biol 5(6): 622–624. [DOI] [PubMed] [Google Scholar]

[b70] 70. Harman D (1972) The biologic clock: the mitochondria J Am Geriatr Soc 20: 145–147. [DOI] [PubMed] [Google Scholar]

[b71] 71. Harper PS (1991) Huntington's Disease, W. B. Saunders: London . [Google Scholar]

[b72] 72. Harris JJ, Perham RN (1963) Studies on glyceraldehyde‐3‐phosphate dehydrogenases. Biochem J 89: 60–64. [Google Scholar]

[b73] 73. Hayden MR (1981) Huntington's chorea, Springer‐Verlag: London, Berlin, Heidelberg . [Google Scholar]

[b74] 74. Hayden MR (1991) Huntington Disease. In: Textbook of Internal Medicine, Kelley WN (ed.), 2nd Edition, pp. 2179–2181, J. B. Lippincott Co.: Philadelphia . [Google Scholar]

[b75] 75. Hedreen JC, Folstein SE (1995) Early loss of neostriatal striosome neurons in Huntington's disease. J Neuropathol Exp Neurol 54: 105–120. [DOI] [PubMed] [Google Scholar]

[b76] 76. Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM, Kruse K (1996) The clinical and molecular spectrum of androgen insensitivity syndromes. Am J Med Genet 63: 218–222. [DOI] [PubMed] [Google Scholar]

[b77] 77. Holtzman DA, Yang S, Drubin DG (1993) Synthetic‐lethal interactions identify two novel genes, SLA1 and SLA2, that control membrane cytoskeleton assembly in Saccharomyces cerevisiae. J Cell Biol 122(3): 635–644. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b78] 78. Hope BT, Michael GJ, Knigge KM, Vincent SR (1991) Neuronal NADPH‐diaphorase is a nitric oxide synthase. Proc Natl Acad Sci USA 88: 2811–2814. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b79] 79. Huitorel P, Pantoloni D (1985) Bundling of microtubules by glyceraldehyde‐e‐phosphate dehydrogenase and its modulation by ATP. Eur J Biochem 150: 265–269. [DOI] [PubMed] [Google Scholar]

[b80] 80. Huntington Study Group (1995) Huntington Study Group (HSG) policy on non‐disclosure of CAG trinucleotide repeat length (CAGn) genetic (DNA) information as formulated by the HSG Committee of Michael Conneally, Kimberly Quaid, Nancy Wexler and the HSG Executive Committee (Anne Young, John Penney, Dennis Choi, Karl Kieburtz, David Oakes, Ira Shoulson ‐ Chair) and as reviewed and approved by the HSG members (December 3, 1994 and February 13, 1995), (UnPub).

[b81] 81. Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971–983. [DOI] [PubMed] [Google Scholar]

[b82] 82. Huntington G (1872) On chorea. Med Surg Rep 26: 317–321. [Google Scholar]

[b83] 83. Iked A H, Yamaguchi M, Sugai S, Aze Y, Narurniya S, Kakizuka A (1996) Expanded polyglutamine in the Machado‐Joseph disease protein induces cell death in vitro and in vivo. Nature Genet 13(2): 196–202. [DOI] [PubMed] [Google Scholar]

[b84] 84. Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR (1993) Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology 43(12): 2689–2695. [DOI] [PubMed] [Google Scholar]

[b85] 85. Jodice C, Malaspina P, Persichetti F, Novelletto A, Spadaro M, Giunti P, Morocutti C, Terrenato L, Harding AE, Frontali M (1994) Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia 1. Am J Hum Genet 54: 959–965. [PMC free article] [PubMed] [Google Scholar]

[b86] 86. Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR (1996) Huntingtin is ubiquitinated and interacts with a specific ubiquitin conjugated enzyme. J Biol Chem 271 (32): 19385–19394. [DOI] [PubMed] [Google Scholar]

[b87] 87. Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, Kazemi‐Esfarjani P, Lynn FC, Wellington C, Metzler M, Goldberg YP, Kanazawa I, Gietz RD, Hayden MR (1997) HIP1, a human homolog of S. cerevisiae Sla2p, interacts with membrane‐associated huntingtin in the brain. Nature Genet 16: 44–53. [DOI] [PubMed] [Google Scholar]

[b88] 88. Kamens J, Paskind M, Hugunin M, Talanian RV, Allen H, Banach D, Bump N, Hackett M, Johnston CG, Li P, Mankovich JA, Terranova M, Ghayur T (1995) Identification and characterization of ICH‐2, a novel member of the interleukin‐1 beta‐converting enzyme family of cysteine proteases. J Biol Chem 270(25): 15250–15256. [DOI] [PubMed] [Google Scholar]

[b89] 88b. Kluck RM, Bossy‐Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: aprimary site for Bcl‐2 regulation of apoptosis. Science 275: 1132–1136. [DOI] [PubMed] [Google Scholar]

[b90] 89. Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, Saito M, Tomoda A, Miike T, Naito H, Ikuta F, Tsuji S (1994) Unstable expansion of CAG repeat in hereditary dentatorubral‐pallidoluysian atrophy (DRPLA). Nature Genet 6: 9–13. [DOI] [PubMed] [Google Scholar]

[b91] 90. Komure O, Sano A, Nishino N, Yamauchi N, Ueno S, Konodoh K, Sano N, Takahashi M, Murayarna N, Kondo I, Nagafuchi S, Yamada M, Kanazawa I (1995) DNA analysis in hereditary dentatorubral‐pallidoluysian atrophy: Correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. Neurology 45: 143–149. [DOI] [PubMed] [Google Scholar]

[b92] 91. Koroshetz WJ, Jankins BG, Rosen BR, Beal MF (1996) Energy metabolism defects in Huntington's disease and effects of coenzyme Q10. Ann Neurol 41: 160–165. [DOI] [PubMed] [Google Scholar]

[b93] 92. Korsmeyer SJ (1995) Regulators of cell death. Trends Genet 11: 101–105. [DOI] [PubMed] [Google Scholar]

[b94] 93. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN (1993) Bcl‐2/Bax: a rheostat that regulates an anti‐oxidant pathway and cell death. Semin Cancer Biol 4: 327–332. [PubMed] [Google Scholar]

[b95] 94. Koshy B, Matilla T, Burright EN, Merry DE, Fischbeck KH, Orr HT, Zoghbi HY (1996) Spinocerebellar ataxia type‐1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde‐3‐phosphate dehydrogenase. Hum Mol Genet 5(9): 1311–1318. [DOI] [PubMed] [Google Scholar]

[b96] 95. Koutouzis TK, Borlongan CV, Freeman TB, Cahill DW, Sanberg PR (1994) Intrastriatal 3‐nitropropionic acid: a behavioral assessment. Neuro Report 5(17): 2241–2245. [DOI] [PubMed] [Google Scholar]

[b97] 96. Kowall NW, Ferrante RJ, Martin JB (1987) Patterns of cell loss in Huntington's disease. TINS 10: 24–29. [Google Scholar]

[b98] 97. Kramer PL, Yue Q, Gancher ST, Nutt JG, Baloh R, Smith E, Browne D, Bussey K, Lovrien E, Nelson S, Litt M (1995) A locus for the nystagmus‐associated form of episodic ataxia maps to an 11‐cM region on chromosome 19p (letter to the editor). Am J Hum Genet 57: 182–185. [PMC free article] [PubMed] [Google Scholar]

[b99] 98. Kuida K, Zheng TS, Na S, Kuan C‐y, Yang D, Karasuyama H, Rakic P, Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32‐deficient mice. Nature 384(6607): 368–372. [DOI] [PubMed] [Google Scholar]

[b100] 99. La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa‐Petrusewicz I, Yee W‐C, Fischbeck KH (1992) Meiotic stability and genotype‐phenotype correlation of the trinucleotide repeat in X‐linked spinal and bulbar muscular atrophy. Nature Genet 2: 301–304. [DOI] [PubMed] [Google Scholar]

[b101] 100. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fishbeck KH (1991) Androgen receptor gene mutations in X‐linked spinal and bulbar muscular atrophy. Nature 352: 77–79. [DOI] [PubMed] [Google Scholar]

[b102] 101. Lange H, Thorner G, Hopf A, Schroder KF (1976) Morphometric studies of the neuropathological changes in choreatic diseases. J Neurol Sci 28: 401–425. [DOI] [PubMed] [Google Scholar]

[b103] 102. Lanska DJ, Lanska MJ, Lavine L, Schoenberg BS (1988) Conditions associated with Huntington's disease at death. A case‐control study. Arch Neurol 45: 878–880. [DOI] [PubMed] [Google Scholar]

[b104] 103. Legius E, Cuppens H, Dierick H, Van Zandt K, Dom R, Fryns J‐P, Evers‐Kiebooms G, Decruyenaere M, Demyttenaere K, Marynen P, Cassiman J‐J (1994) Limited expansion of the (CAG)n repeat of the Huntington gene: A premutation (?). Eur J Hum Genet 2: 44–50. [DOI] [PubMed] [Google Scholar]

[b105] 104. Li X‐J, Li S‐H, Sharp AH, Nucifora FC Jr., Schilling G, Lanahan A, Worley P, Snyder SH, Ross CA (1995) A hunt‐ingtin‐associated protein enriched in brain with implications for pathology. Nature 378: 398–402. [DOI] [PubMed] [Google Scholar]

[b106] 105. Li X‐J, Sharp AH, Li S‐H, Dawson TM, Snyder SH, Ross CA (1996) Huntingtin‐associated protein (HAP1): Discrete neuronal localization resemble those of neuronal nitric oxide synthase. Proc Natl Acad Sci USA 93: 4839–4844. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b107] 105b. Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell‐free extracts: requirement for dATP and cytochrome c. Cell 86(1): 147–157. [DOI] [PubMed] [Google Scholar]

[b108] 106. Llinas R, Sugimori M, Hillman DE, Cherksey B (1992) Distribution and functional significance of the P‐type, voltage‐dependent Ca2+ channels in the mammalian central nervous system. TINS 15: 351–355. [DOI] [PubMed] [Google Scholar]

[b109] 107. Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M (1991) 3‐nitropropionic acid‐ exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 18: 492–498. [DOI] [PubMed] [Google Scholar]

[b110] 108. Ludolph AC, Seelig MO, Ludolph A, Novitt P, Allen CN, Spencer PS, Sabri MI (1992) 3‐Nitropropionic acid decreases cellular energy levels and causes neuronal degradation in cortical explants. Neurodegen 1: 21–28. [Google Scholar]

[b111] 109. Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, Dawson DM, Sudarsky L, Guimaraes J, Loureiro JEL, Nezarati MM, Corwin LI, Lopes‐Cendes I, Rooke K, Rosenberg R, MacLeod P, Farrer LA, Sequeiros J, Rouleau GA (1995) Correlation between CAG repeat length and clinical features in Machado‐Joseph disease. Am J Hum Genet 57: 54–61. [PMC free article] [PubMed] [Google Scholar]

[b112] 110. MacMillan JC, Snell RG, Tyler A, Houlihan GD, Fenton I, Cheadle JP, Lazarou LP, Shaw DJ, Harper PS (1993) Molecular analysis and clinical correlations of the Huntington's disease mutation. Lancet 342: 954–958. [DOI] [PubMed] [Google Scholar]

[b113] 111. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD Gene with an Expanded CAG Repeat is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice. Cell 87: 493–506. [DOI] [PubMed] [Google Scholar]

[b114] 112. Martin SJ, Finucane DM, Amarante‐Mendes GP, O'Brien GA, Green DR (1996) Phosphatidylserine externalization during CD95‐induced apoptosis of cells and cytoplasts requires ICE/CED‐3 protease activity. J Biol Chem 271(46): 28753–28756. [DOI] [PubMed] [Google Scholar]

[b115] 113. Martin SJ, Green DR (1995) Protease Activation during Apoptosis: Death by a Thousand Cuts Cell 82: 349–352. [DOI] [PubMed] [Google Scholar]

[b116] 113b. Martin SJ, Newmeyern DD, Mathias S, Farschon DM, Wang HG, Reed JC, Kolesnick RN, Green DR (1995) Cell‐free reconstitution of Fas‐, UV radiation‐ and ceramide‐induced apoptosis. EMBO Journal 14(21): 5191–5200. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b117] 114. Maruyama H, Nakamura S, Matsuyama Z, Sakai T, Doyu M, Sobue G, Seto M, Tsujihata M, Oh‐i T, Nishio T, Sunohara N, Takahaski R, Hayashi M, Nishino I, Ohtake T, Oda T, Nishimura M, Saida T, Matsumoto H, Baba M, Kawaguchi Y, Kakizuka A, Kawakami H (1995) Molecular features of the CAG repeats and clinical manifestation of Machado‐Joseph disease. Hum Mol Genet 4(5): 807–812. [DOI] [PubMed] [Google Scholar]

[b118] 115. Matsuishi T, Sakai T, Naito E, et al (1996) Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado‐Joseph disease. Acta Neurol Scand 93: 72–75. [DOI] [PubMed] [Google Scholar]

[b119] 116. Mecicci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC, Beal MF (1993) Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain. Ann Neurol 34: 609–616. [DOI] [PubMed] [Google Scholar]

[b120] 117. Mejean C, Pons F, Benyamin Y, Roustan C (1989) Antigenic prebes locate binding sites for the glycolutic enzymes glyceraldehyde‐3‐phosphate dehydrogenase, aldolase and phosphofructokinase on the actin monomer in microfilaments. Biochem J 264: 671–677. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b121] 118. Menzies RA, Gold PH (1971) The turnover of mitochondria in a variety of tissues of young adult and aged rats. J Biol Chem 246: 2425–2429. [PubMed] [Google Scholar]

[b122] 119. Meyer‐Siegler K, Mauro DJ, Seal G, Wurzer J, DeRiel JK, Sirover MA (1991) A human nuclear uracil DNA glycosylase is the 37‐kDa subunit of glyceraldehyde‐3‐phosphate dehydrogenase. Proc Natl Acad Sci USA 88: 8460–8464. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b123] 120. Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M, Thompson CB (1997) Bcl‐xL forms an ion channel in synthetic lipid membranes. Nature 385: 353–357. [DOI] [PubMed] [Google Scholar]

[b124] 121. Mori Y, Friedrich T, Kim M‐S, Mikami A, Nakai J, Ruth P, Bosse E, Hofmann F, Flockerzi V, Furiuchi T, Mikoshiba K, Imoto K, Tanabe T, Numa S (1991) Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350: 398–402. [DOI] [PubMed] [Google Scholar]

[b125] 122. Munday NA, Vaillancourt JP, Ali A, Casano FJ, Miller DK, Molineaux SM, Yamin T‐T, Yu VL, Nicholson DW (1995) Molecular cloning and pro‐apoptotic activity of ICEreIII and ICEreIII, members of the ICE/CED‐3 family of cysteine proteases. J Biol Chem 270(26): 15870–15876. [DOI] [PubMed] [Google Scholar]

[b126] 123. Munn AL. Stevenson BJ, Geli MI, Reizman H (1996) end5, end6, and end7: Mutations that cause actin derealization and block the internalization step of endocyto‐sis in Saccharomyces cerevisiae. Mol Biol Cell 6: 1721–1742. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b127] 124. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko NJ, Scaffidi C, Bretz JD, Zhang M, Gentz R, et al. (1996) Flice, a novel FADD‐homologous ICE/CED‐3 like protease, is recruited to the CD95 (Fas/APO‐1) death‐inducing signaling complex. Cell 85: 817–827. [DOI] [PubMed] [Google Scholar]

[b128] 125. Myers RH, Leavitt J, Karner LA, Farrer L, Jagedeesh J, McFarlane H, Mastromouro CA, Mark RJ, Gusella JF (1989) Homozygore for Huntington disease. Am J Hum Genet 45: 615–618. [PMC free article] [PubMed] [Google Scholar]

[b129] 126. Na S, Hincapie M, McCusker JH, Haber JE (1995) MOP2 (SLA2) affects the abundance of the plasma membrane H+‐ATPase of Saccharomyces cerevisiae. J Biol Chem 270(12): 6815–6823. [DOI] [PubMed] [Google Scholar]

[b130] 127. Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, Tanaka Y, Kirushima H, Umino K, Kurosawa H, Furukawa T, Hikei K, Inoue T, Sano A, Komure O, Takahashi M, Yoshizawa T, Kanazawa I, Yamada M (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nature Genet 6: 14–18. [DOI] [PubMed] [Google Scholar]

[b131] 128. Nagy E, Rigby WF (1995) Glyceraldehyde‐e‐phosphate dehydrogenase selectively binds AU‐rich RNA in the NAD(+)‐binding region (Rossmann fold). J Biol Chem 270: 2755–2763. [DOI] [PubMed] [Google Scholar]

[b132] 129. Nance MA (1996) Huntington disease ‐ another chapter rewritten. Editorial review. Am J Hum Genet 59(1): 1–6. [PMC free article] [PubMed] [Google Scholar]

[b133] 130. Nasir J, Goldberg YP, Hayden MR (1996) Huntington disease: new insights into the relationship between CAG expansion and disease. Invited Review, Hum Mol Genet 5: 1431–1435. [DOI] [PubMed] [Google Scholar]

[b134] 131. Nasir S, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borouski A, Marth JD, Phillips AG, Hayden MR (1995) Targeted disruption of the murine Huntington disease gene results in early post‐implantation embryonic lethality and behavioral and morphological abnormalities in heterozygotes. Cell 81: 811–823. [DOI] [PubMed] [Google Scholar]

[b135] 131b. Newmeyer DD, Farschon DM, Reed JC (1994) Cell‐free apoptosis in Xeniopus egg extracts: inhibition by Bcl‐2 and requirement for an organelle fraction enriched in mitochondria. Cell 79: 353–364. [DOI] [PubMed] [Google Scholar]

[b136] 132. Nicholson DW (1996) ICE/CED3‐like proteases as therapeutic targets for the control of inappropriate apoptosis. Nature Biotech 14: 297–301. [DOI] [PubMed] [Google Scholar]

[b137] 133. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson ME, Yamin T‐T, Yu VL, Miller DK (1995) Identification and inhibition of the ICE/CED‐3 protease necessary for mammalian apoptosis. Nature 376: 37–43. [DOI] [PubMed] [Google Scholar]

[b138] 134. Norremolle A, Riess O, Epplen JT, Fenger K, Hasholt L, Sorenson SA (1993) Trinucleotide repeat elongation in the Huntington gene in Huntington disease patients from 71 Danish families. Hum Mol Genet 2: 1475–1476. [DOI] [PubMed] [Google Scholar]

[b139] 135. Novelletto A, Persichetti F, Sabbadini G, Mandich P, Bellone E, Ajmar F, Pergola M, Dei Sanno L., MacDonald ME, Gusella JF, Frcntali M (1994) Analysis of the trinucleotide repeat expansion in Italian families affected with Huntington disease. Hum Mol Genet 3(1): 93–98. [DOI] [PubMed] [Google Scholar]

[b140] 136. Onodera O, Roses AD, Tsuji S, Vance JM, Strittmatter WJ, Burke JR (399) Toxicity of expanded polyglutamine‐domain proteins in Escherichia coli. FEBS Letters 135: 139. [DOI] [PubMed] [Google Scholar]

[b141] 137. Palfi S, Ferrante RJ, Brouillet E, Beal MF, Dolan R, Guyot MC, Peschanski M, Hantraye P (1996) Chronic 3‐nitro‐propionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington's disease. J Neuro 16(9): 3019–3025. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b142] 138. Parker, W. D. , Boyson SJ, Luder AS, Parks JK (1990) Evidence for a defect in NADH: uibiquinone oxidoreduc‐tase (complex I) in Huntington's disease. Neurology 40: 1231–1234. [DOI] [PubMed] [Google Scholar]

[b143] 139. Perutz MF, Johnson T, Suzuki M, Finch JT (1994) Glutamine repeats as polar zippers: their possible rele in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 91: 5355–5358. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b144] 140. Petit PX, Susin S‐A, Zamzami N, Mignotte B, Kroemer G (1996) Mitochondria and programmed cell death: back to the future. FEBS Letters 396: 7–13. [DOI] [PubMed] [Google Scholar]

[b145] 141. Protera‐Cailliau C, Hedreer, JC , Price DL, Koliatsos VE (1995) evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci 15(5): 3775–3787. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b146] 142. Ranum LPW, Chung M‐y, Banfi S, Bryer A, Schut LJ, Ramesar R, Duvick LA, McCall AE, Subramcny SH, Goldfarb L, Gomez C, Sandkuijl LA, Orr HT, Zoghbi HY (1994) Molecular and clinical correlations in spinocerebellar ataxia type 1 (SCA1): evidence for familial effects on the age of onset. Am J Hum Genet 55: 244–252. [PMC free article] [PubMed] [Google Scholar]

[b147] 143. Reed JC (1994) Bcl‐2 and the regulation of programmed cell death (Review). J Cell Biol 124(1–2): 1–6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b148] 144. Richardson EP Jr. (1990) Huntington's disease: some recent neuropathological studies. Neuropathol Appl Neurobiol 16: 451–460. [DOI] [PubMed] [Google Scholar]

[b149] 145. Richfield EK, Maguire‐Zeiss KA, Vonkeman HE, Voorn P (1995) Preferential loss of preproenkephalin versus pre‐ protakykinin neurons from the striatum of Huntington's disease patients. Ann Neurol 38: 852–861. [DOI] [PubMed] [Google Scholar]

[b150] 146. Ronai Z (1993) Glycolytic enzymes as DNA binding proteins. Int J Biochem 25: 1073–1076. [DOI] [PubMed] [Google Scholar]

[b151] 147. Ross CA (1995) When more is less: Pathogenesis of glu‐tamine repeat neurodegenerative diseases. Neuron 15: 493–496. [DOI] [PubMed] [Google Scholar]

[b152] 148. Rubinsztein DC, Barton DE, Davison BCC, Ferguson‐Smith MA (1993) Analysis of the huntingtin gene reveals a trinucleotide‐length polymorphism in the region of the gene that contains two CCG‐rich stretches and a correlation between decreased age of onset of Huntington's disease and CAG repeat number. Hum Mol Genet 2: 1713–1715. [DOI] [PubMed] [Google Scholar]

[b153] 149. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman J‐J, Chotai K, Connarty M, Craufurd D, Curtis A, Curtis D, Davidson MJ, Differ A‐M, Dode C, Dodge A, Frontali M, Ranen MG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Jackson A, Kaplan J‐C, Losekoot M, MacMillan JC, Morrison P, Trottier Y, Novelletto A, Simpson SA, Theilmann J, Whittaker JL, Folstein SE, Ross CA, Hayden MR (1996) Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington's disease gene (HD) reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am J Hum Genet 59: 16–22. [PMC free article] [PubMed] [Google Scholar]

[b154] 150. Schiffer D, Attanasino A, Chio A, Migheli A, Pezzulo T (1994) Ubiquitinated dystrophic neurites suggest corticospinal derangement in patients with amyotrophic lateral sclerosis. Neuro Lett 180: 21–24. [DOI] [PubMed] [Google Scholar]

[b155] 151. Schulz JB, Matthews RT, Jenkins BG, Ferrante R. J., Siewk D, Henshaw DR, Cipolloni PB, Mecocci P, Kowall NW, Rosen BR, Beal MF (1995) Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neuro 15(12): 8419–8429. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b156] 152. Schulze H, Schuler A, Stüber, Dobeli H, Langen H, Huber G (1993) Rat Brain Glyceraldehyde‐3‐Phosphate Dehydrogenase Interacts with the Recombinant Cytoplasmic Domain of Alzheimer's beta‐Amyloid Precursor Protein. J Neurochem 60(5): 1915–1992. [DOI] [PubMed] [Google Scholar]

[b157] 153. Servadio A, Koshy B, Armstrong D, Antalffy B, Orr HT, Zoghbi HY (1995) Expression analysis of the ataxin‐1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genef 10(1): 94–98. [DOI] [PubMed] [Google Scholar]

[b158] 154. Shimizu S, Eguchi Y, Kamiike W, Waguri S, Uchiyama YI, Matsuda H, Tsujimoto Y (1996) Bcl‐2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. Oncogene 13: 21–29. [PubMed] [Google Scholar]

[b159] 155. Sigiyama H, Hainfeller JA, Yoshimura M, Budka H (1994) Neocortical changes in Parkinson's disease, revisited. Clin Neuropath 13: 55–59. [PubMed] [Google Scholar]

[b160] 156. Simpson SA, Davidson MJ, Barron LH (1993) Huntington's disease in Grampian region: correlation of the CAG repeat number and the age of onset of the disease. J Med Genet 30(12): 1014–1017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b161] 157. Singh R, Green MR (1993) Sequence specific binding of transfer RNA by glyceraldehyde‐3‐phosphate dehydrogenases. Science 259: 365–368. [DOI] [PubMed] [Google Scholar]

[b162] 158. Skulachev VP (1996) Why are mitochondria involved in apoptosis FEBS Letters 387: 7–10. [DOI] [PubMed] [Google Scholar]

[b163] 159. Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P, MacDonaid ME, Gusella JF, Harper PS, Shaw DJ (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nature Genet 4(4): 393–397. [DOI] [PubMed] [Google Scholar]

[b164] 160. Somers M, Engelborghs Y, Baert J (1990) Analysis of the binding of glyceraldehyde‐3‐phosphate dehydrogenase to microtubules, the mechanism of bundle formation and the linkage effect. Eur J Biochem 193: 437–444. [DOI] [PubMed] [Google Scholar]

[b165] 161. Song Q, Wei T, Lees‐Miller S, Alnemri E, Watters D, Lavin MF (1997) Resistance of actin to cleavage during apoptosis. Proc Natl Acad Sci USA 94(1): 157–162. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b166] 162. Soong B‐W, Wang JT (1995) A comparison of the Huntington's disease associated trinucleotide repeat between Chinese and white populations. J Med Genet 32: 404–408. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b167] 163. Soong N‐W, Hinton DR, Cortpassi G, Arnheim N (1992) Mosaicism for a specific mitochondrial DNA mutation in adult human brain. Nature Genet 2: 318–323. [DOI] [PubMed] [Google Scholar]

[b168] 164. Srinivasula SM, Fernandes‐Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (1996) The Ced‐3/Interleukin 1beta converting enzyme‐like homolog Mch6 and the lamin‐cleaving enzyme Mch2 alpha are substrates for tne apoptotic mediator CPP32. J Biol Chem 271(43): 27099–27106. [DOI] [PubMed] [Google Scholar]

[b169] 165. Stine OC, Pleasant N, Franz ML, Abbott MH, Folstein SE, Ross CA (1993) Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT‐15 Hum Mol Genef 2(10): 1547–1549. [DOI] [PubMed] [Google Scholar]

[b170] 166. Taddei N, Liguri G, Sorbi S, Amaducci L, Camici G, Cecchi C, Ramponi G (1993) Cerebral soluble ubiquitin is increased in patients with Alzheimer's disease. Neuro Lett 151: 158–161. [DOI] [PubMed] [Google Scholar]

[b171] 167. Takai D, Inoue K, Shisa H, Kagawa Y, Hayashi JI (1995) Age‐associated changes of mitochondrial translation and respiratory function in mouse brain. Biochem & Biophys Res Comm 217: 668–674. [DOI] [PubMed] [Google Scholar]

[b172] 168. Takiyama Y, Igarashi S, Rogaeva EA, Endo K, Rogaev EI, Tanaka H, Sherrington R, Sanpei K, Liang Y, Saito M, Tsuda T, Takano H, Ikeda M, Lin C, Chi H, Kennedy JL, Lang AE, Wherrett JR, Segawa M, Nomura Y, Yuasa T, Weissenbach J, Yoshida M, Nishizawa M, Kidd KK, Tsuji S, St George‐Hyslop PH (1995) Evidence for inter‐generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado‐Joseph disease. Hum Mol Genet 4(7): 1137–1146. [DOI] [PubMed] [Google Scholar]

[b173] 169. Tellez‐Nagel I, Johnson AB, Terry RD (1973) Ultrastructural and histochemical study of cerebral biopsies in Huntington's chorea. Adv Neurol 1: 387–397. [Google Scholar]

[b174] 170. Tewari M, Quc. n LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirer GG, Salvesen GS, Dixit VM (1995) Yama/CPP32beta, a Mammalian Homolog of CED‐3, Is a CrmA‐lnhibitable Protease That Cleaves the Death Substrate Poly(ADP‐Ribose) Polymerase. Cell 81: 801–809. [DOI] [PubMed] [Google Scholar]

[b175] 171. Thomas LB, Gates DJ, Richfield EK, O'Brien TF, Schweitzer JB, Steindler DA (1995) DNA End Labeling (TUNEL) in Huntington's Disease and Other Neuropathological Conditions. Exp Neurol 133: 265–272. [DOI] [PubMed] [Google Scholar]

[b176] 172. Trottier Y, Biancalana V, Mandel JL (1994) Instability of CAG repeats in Huntington's disease: relationship to parental transmission and age of onset. J Med Genet 31(5): 377–382. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b177] 173. Vahedi K, Joutel A, Van Bogaert P, Ducros A, Maciazeck J, Bach JF, Bousser MG, Toumier‐Lasserve E (1995) A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 37(3): 289–293. [DOI] [PubMed] [Google Scholar]

[b178] 174. Vincenz C, Dixit VM (1997) Fas‐associated death domain protein interleukin‐1 beta‐converting enzyme 2 (FLICE2), an ICE/CED‐3 homologue, is proximally involved in CD95‐ and p55‐mediated death signaling. J Biol Chem 272(10): 6578–6583. [DOI] [PubMed] [Google Scholar]

[b179] 175. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. (1985) Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 44: 559–577. [DOI] [PubMed] [Google Scholar]

[b180] 176. Wallace DC (1992) Mitochondrial Genetics: A paradigm for aging and degenerative diseases Science 256: 628–632. [DOI] [PubMed] [Google Scholar]

[b181] 177. Wang L, Miura M, Bergeron L, Zhu H, Yuan J (1994) Ich‐1, an Ice/ced‐3‐related gene, encodes both positive and negative regulators of programmed cell death. Cell 78: 739–750. [DOI] [PubMed] [Google Scholar]

[b182] 178. Wang X, Zelenski NG, Yang J, Sakai J, Brown MS, Goldstein JL (1996) Cleavage of sterol regulatory element binding proteins (SREBPs) by CPP32 during apoptosis. Embo J 15: 1012–1020. [PMC free article] [PubMed] [Google Scholar]

[b183] 179. Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, Tait D, Colicelli J, Lehrach H (1997) HIP1: A huntingtin interacting protein isolated by the yeast two‐hybrid system. Hum Mol Genet 6: 487–495. [DOI] [PubMed] [Google Scholar]

[b184] 180. Wexler NS, Young AB, Tanzi RE, Travers H, Starosta‐Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA (1987) Homozygotes for Huntington's disease. Nature 326: 194–197. [DOI] [PubMed] [Google Scholar]

[b185] 181. Wong‐Riley MTT (1989) Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. TINS 12(3): 94–101. [DOI] [PubMed] [Google Scholar]

[b186] 182. Wu D, Wallen HD, Nunez G (1997) Interaction and regulation of subcellular localization of CED‐4 by CED‐9. Science 275: 1126–1129. [DOI] [PubMed] [Google Scholar]

[b187] 183. Yang E, Korsmeyer SJ (1996) Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 88(2): 386–401. [PubMed] [Google Scholar]

[b188] 183b. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T‐I, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl‐2: Release of cytochrome c from mitochondria blocked. Science 275: 1129–1132. [DOI] [PubMed] [Google Scholar]

[b189] 184. Yuan J‐Y, Shaham S, Ledoux S, Ellis HJM, Horvitz HR (1993) The C. elegans cell death gene ced‐3 encodes a protein similar to mammalian interleukin‐1 beta‐converting enzyme. Cell 75: 641–652. [DOI] [PubMed] [Google Scholar]

[b190] 185. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroerer G (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182: 367–377. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b191] 186. Zeitlin S, Liu J‐P, Chapman DL, Papaioannou VE. Efstratiadis A (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature Genet 11: 155–162. [DOI] [PubMed] [Google Scholar]

[b192] 187. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amox D, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alphalA‐voltage‐dependent calcium channel. Nature Genet 15: 62–69. [DOI] [PubMed] [Google Scholar]

[b193] 188. Zuhlke C, Riess O, Shroder K, Siedlaczck I, Epplen JT, Engel W, Thies U (1993) Expansion of the (CAG)n repeat causing Huntington's disease in 352 patients of German origin. Hum Mol Genet 2: 1467–1469. [DOI] [PubMed] [Google Scholar]

PERMALINK

Toward Understanding the Molecular Pathology of Huntington's Disease

Cheryl L Wellington

Ryan R Brinkman

John R O'Kusky

Michael R Hayden

Abstract

Full Text

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Toward Understanding the Molecular Pathology of Huntington's Disease

Cheryl L Wellington

Ryan R Brinkman

John R O'Kusky

Michael R Hayden

Abstract

Full Text

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases