Abstract
Polyglutamine expansion is now recognized to be a major cause of inherited human neurodegenerative disease. The polyglutamine expansion diseases identified so far are slowly progressive disorders in which distinct yet overlapping brain regions are selectively vulnerable to degeneration. Despite their clinical differences these diseases likely share a common pathogenic mechanism, occurring at the protein level and centered on an abnormal conformation of expanded polyglutamine in the respective disease proteins. Recently there has been remarkable progress in our understanding of polyglutamine disease, but still there are many unanswered questions. In this review, I first outline some of the shared features of polyglutamine diseases and then discuss several issues relevant to an understanding of pathogenesis, paying particular attention to possible mechanisms of neurotoxicity.
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References
- 1. Chai Y , Koppenhafer S , Shoesmith S , Perez M , Paulson H ( 1999. ) Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro . Hum Mol Genet 8 : 673 – 82 . [DOI] [PubMed] [Google Scholar]
- 2. Chai Y , Koppenhafer S , Bonini N , Paulson H ( 1999. ) Analysis of the role of heat shock protein (Hsp) chaperones in polyglutamine disease . J Neurosci 19 : 10338 – 10347 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Cooper JK , Schilling G , Peters MF , Herring WJ , Sharp AH , Kaminsky Z , Masone J , Khan FA , Delanoy M , Borchelt DR , Dawson VL , Dawson TM , Ross CA ( 1998. ) Truncated N‐terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture . Hum Mol Genet 7 : 783 – 790 . [DOI] [PubMed] [Google Scholar]
- 4. Cummings CJ , Mancini MA , Antalffy B , DeFranco DB , Orr HT , Zoghbi HY ( 1998. ) Chaperone suppression of ataxin1 aggregation and altered subcellular proteosome localization imply protein misfolding in SCA1 . Nat Genet 19 : 148 – 154 . [DOI] [PubMed] [Google Scholar]
- 5. Davies SW , Turmaine M , Cozens BA , DiFiglia M , Sharp AH , Ross CA , Scherzinger E , Wanker EE , Mangiarini L , Bates GP ( 1997. ) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation . Cell 90 : 537 – 548 . [DOI] [PubMed] [Google Scholar]
- 6. DiFiglia M , Sapp E , Chase KO , Davies SW , Bates GP , Vonsattel JP , Aronin N ( 1997. ) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain . Science 277 : 1990 – 1993 . [DOI] [PubMed] [Google Scholar]
- 7. Ellerby LM , Andrusiak RL , Wellington CL , Hackam AS , Propp SS , Wood JD , Sharp AH , Margolis RL , Ross CA , Salvesen GS , Hayden MR , Bredesen DE. ( 1999. ) Cleavage of Atrophin‐1 at Caspase Site Aspartic Acid 109 Modulates Cytotoxicity J Biol Chem 274 : 8730 – 8736 . [DOI] [PubMed] [Google Scholar]
- 8. Ellerby LM , Hackam AS , Propp SS , Ellerby HM , Rabizadeh S , Cashman NR , Trifiro MA , Pinsky L , Wellington CL , Salvesen GS , Hayden MR , Bredesen DE. ( 1999. ) Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity . J Neurochem 72 ( 1 ): 185 – 95 . [DOI] [PubMed] [Google Scholar]
- 9. Evert BO , Wüllner U , Schulz JB , Weller M , Groscurth P , Trottier Y , Brice A , Klockgether T ( 1999. ) High level expression of expanded full‐length ataxin‐3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells . Hum Molec Genet 8 : 1169 – 1176 . [DOI] [PubMed] [Google Scholar]
- 10. Faber PW , Alter JR , MacDonald ME , Hart AC. ( 1999. ) Polyglutamine‐mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron . PNAS 96 : 179 – 184 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Goldberg YP , Nicholson DW , Rasper DM , Kalchman MA , Koide HB , Graham RK , Bromm M , Kazemi‐Esfarjani P , Thornberry NA ( 1996. ) Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract . Nat Genet 13 : 442 – 449 . [DOI] [PubMed] [Google Scholar]
- 12. Hodgson JG , Agopyan N , Gutekunst CA , Leavitt BR , LePiane F , Singaraja R , Smith DJ , Bissada N , McCutcheon K , Nasir J , Jamot L , Li XJ , Stevens ME , Rosemond E , Roder JC , Phillips AG , Rubin EM , Hersch SM , Hayden MR. ( 1999. ) A YAC mouse model for Huntington's disease with full‐length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration . Neuron 23 ( 1 ): 181 – 92 . [DOI] [PubMed] [Google Scholar]
- 13. Huynh D , Del Bigio M , Ho D , Pulst S‐M ( 1999. ) Expression of ataxin 2 in brains from normal individuals and patients with Alzheimer disease and spinocerebellar ataxia 2 (SCA2) . Ann Neurol 45 : 232 – 41 . [DOI] [PubMed] [Google Scholar]
- 14. Jackson GR , Salecker I , Dong X , Yao X , Arnheim N , Faber PW , MacDonald ME , Zipursky SL ( 1998. ) Polyglutamineexpanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons . Neuron 21 : 633 – 642 . [DOI] [PubMed] [Google Scholar]
- 15. Ikeda H , Yamaguchi M , Sugai S , Aze Y , Narumiya S , Kakizuka A ( 1996. ) Expanded polyglutamine in the MachadoJoseph disease protein induces cell death in vitro and in vivo . Nat Genet 13 : 196 – 202 . [DOI] [PubMed] [Google Scholar]
- 16. Ishikawa K , Fujigasaki H , Saegusa H , Ohwada K , Fujita T , Iwamoto H , Komatsuzaki Y , Toru S , Toriyama H , Watanabe M , Ohkoshi N , Shoji S , Kanazawa I , Tanabe T , Mizusawa H ( 1999. ) Abundant expression and cytoplasmic aggregations of [alpha]1A voltage‐dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6 . Hum Molec Genet 8 : 1185 – 1193 . [DOI] [PubMed] [Google Scholar]
- 17. Kazantsev A , Preisinger E , Dranovsky A , Goldgaber D , Housman D ( 1999. ) Insoluble detergent‐resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells . Proc Natl Acad Sci USA 96 : 11404 – 11409 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Kim M , Lee HS , LaForet G , McIntyre C , Martin EJ , Chang P , Kim TW , Williams M , Reddy PH , Tagle D , Boyce FM , Won L , Heller A , Aronin N , DiFiglia M. ( 1999. ) Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition . J Neurosci 19 ( 3 ): 964 – 73 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Klement IA , Skinner PJ , Kaytor MD , Yi H , Hersch SM , Clark HB , Zoghbi HY , Orr HT ( 1998. ) Ataxin‐1 nuclear localization and aggregation: role in polyglutamineinduced disease in SCA1 transgenic mice . Cell 95 : 41 – 53 . [DOI] [PubMed] [Google Scholar]
- 20. Kobayashi Y , Miwa S , Merry DE , Kume A , Mei L , Doyu M , Sobue G. ( 1998. ) Caspase‐3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length‐dependent manner . Biochem Biophys Res Comm 252 ( 1 ): 145 – 50 , 1998 . [DOI] [PubMed] [Google Scholar]
- 21. LaSpada AR , Wilson EM , Lubahn DB , Harding AE , Fischbeck KH ( 1991. ) Androgen receptor gene mutations in X‐linked spinal and bulber muscular atrophy . Nature 352 : 77 – 79 . [DOI] [PubMed] [Google Scholar]
- 22. Lin X , Cummings CJ , Zoghbi HY ( 1999. ) Expanding Our Understanding of Polyglutamine Diseases through Mouse Models . Neuron 24 : 499 – 502 . [DOI] [PubMed] [Google Scholar]
- 23. 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]
- 24. Martindale D , Hackam A , Wieczorek A , Ellerby L , Wellington C , McCutcheon K , Singaraja R , Kazemi‐Esfarjani P , Devon R , Kim SU , Bredesen DE ( 1998. ) Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates . Nat Genet 18 : 150 – 154 . [DOI] [PubMed] [Google Scholar]
- 25. Merry DE , Kobayashi Y , Bailey CK , Taye AA , Fischbeck KH ( 1998. ) Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy . Hum Mol Genet 7 : 693 – 701 . [DOI] [PubMed] [Google Scholar]
- 26. Miyashita T , Matsui J , Ohtsuka Y , Mami U , Fujishima S , Okamura‐Oho Y , Inoue T , Yamada M. ( 1999. ) Expression of extended polyglutamine sequentially activates initiator and effector caspases . Biochem Biophys Res Comm 257 ( 3 ): 724 – 30 . [DOI] [PubMed] [Google Scholar]
- 27. Moulder KL , Onodera O , Burke JR , Strittmatter WJ , Johnson EM Jr. ( 1999. ) Generation of neuronal intranuclear inclusions by polyglutamine‐GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length . J Neurosci 19 ( 2 ): 705 – 15 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Ona VO , Li M , Vonsattel JP , Andrews LJ , Khan SQ , Chung W , Frey AS , Menon AS , Li XJ , Stieg PE , Yuan J , Penney JB , Young AB , Cha JH , Friedlander RM ( 1999. ) Inhibition of caspase‐1 slows disease progression in a mouse model of Huntington's disease . Nature 399 ( 6733 ): 263 – 267 . [DOI] [PubMed] [Google Scholar]
- 29. Paulson HL ( 1999. ) Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold . Am J Hum Genet 64 : 339 – 345 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Perez M , Paulson H , Pendse S , Saionz S , Bonini N , Pittman R ( 1998. ) Recruitment and the role of nuclear localization in polyglutamine‐mediated aggregation . J Cell Biol 143 : 1457 – 1470 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Perez M , Paulson H , Pittman R ( 1999. ) Nuclear localization of ataxin‐3 alters conformation of the polyglutamine tract . Hum Mol Genet ( in Press ). [DOI] [PubMed] [Google Scholar]
- 32. Perutz MF ( 1999. ) Glutamine repeats and neurodegenerative diseases: molecular aspects Trends Bioch Sci 24 : 58 – 63 . [DOI] [PubMed] [Google Scholar]
- 33. Reddy P , Williams M , Charles V , Garrett L , Pike‐Buchanan L , Whetsell W , Miller G , Tagle D ( 1998. ) Behavioral abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full‐length HD cDNA . Nat Genet 20 : 198 – 202 . [DOI] [PubMed] [Google Scholar]
- 34. Reddy PH , Williams M. , Tagle DA ( 1999. ) Recent advances in understanding the pathogenesis of Huntington's disease . Trends in Neurosci 22 ( 6 ): 248 – 255 . [DOI] [PubMed] [Google Scholar]
- 35. Sanchez I , Xu CJ , Juo P , Kakizaka A , Blenis J , Yuan J ( 1999. ) Caspase‐8 is required for cell death induced by expanded polyglutamine repeats . Neuron 22 ( 3 ): 623 – 33 . [DOI] [PubMed] [Google Scholar]
- 36. Saudou F , Finkbeiner S , Devys D , Greenberg ME ( 1998. ) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions . Cell 95 : 55 – 66 . [DOI] [PubMed] [Google Scholar]
- 37. Scherzinger E , Lurz R , Turmaine M , Mangiarini L , Hollenbach B , Hasenbank R , Bates GP , Davies SW , Lehrach H , Wanker EE ( 1997. ) Huntingtin‐encoded polyglutamine expansions form amyloid‐like protein aggregates in vitro and in vivo . Cell 90 : 549 – 558 . [DOI] [PubMed] [Google Scholar]
- 38. Schilling G , Becher MW , Sharp AH , Jinnah HA , Duan K , Kotzuk JA , Slunt HH , Ratovitski T , Cooper JK , Jenkins NA , Copeland NG , Price DL , Ross CA , Borchelt DR ( 1999. ) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N‐terminal fragment of huntingtin . Hum Mol Genet 8 ( 3 ): 397 – 407 . [DOI] [PubMed] [Google Scholar]
- 39. Stenoien DL , Cummings CJ , Adams HP , Mancini MG , Patel K , DeMartino GN , Marcelli M , Weigel NL , Mancini MA ( 1999. ) Polyglutamine‐expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC‐1, and are suppressed by the HDJ‐2 chaperone . Hum Molec Genet 8 : 731 – 741 . [DOI] [PubMed] [Google Scholar]
- 40. Trottier Y , Lutz Y , Stevanin G , Imbert G , Devys D , Cancel G , Saudou F , Weber C , David G , Tora L , et al. ( 1995. ) Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias . Nature 378 : 403 – 406 . [DOI] [PubMed] [Google Scholar]
- 41. Warrick JM , Paulson HL , Gray‐Board G , Bui QT , Fischbeck KH , Pittman RN , Bonini NM ( 1998. ) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila . Cell 93 : 939 – 949 . [DOI] [PubMed] [Google Scholar]
- 42. Warrick JM , Chan E , Gray‐Board G , Paulson HL , Bonini NM ( 1999. ) Suppression of polyglutamine‐mediated neurodegeneration in Drosophila by the molecular chaperone Hsp70 . Nat Genet ( in Press ). [DOI] [PubMed] [Google Scholar]
- 43. Wellington CL , Ellerby LM , Hackam AS , Margolis RL , Trifiro MA , Singaraja R , McCutcheon K , Salvesen GS , Propp SS , Bromm M , Rowland KJ , Zhang T , Rasper D , Roy S , Thornberry N , Pinsky L , Kakizuka A , Ross CA , Nicholson DW , Bredesen DE , Hayden MR ( 1998. ) Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract . J Biol Chem 273 : 9158 – 9167 . [DOI] [PubMed] [Google Scholar]