Skip to main content
PMC home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1999 Jun 29;354(1386):995–1003. doi: 10.1098/rstb.1999.0451

Are there multiple pathways in the pathogenesis of Huntington's disease?

N Aronin 1, M Kim 1, G Laforet 1, M DiFiglia 1
PMCID: PMC1692615  PMID: 10434298

Abstract

Studies of huntingtin localization in human post-mortem brain offer insights and a framework for basic experiments in the pathogenesis of Huntington's disease. In neurons of cortex and striatum, we identified changes in the cytoplasmic localization of huntingtin including a marked perinuclear accumulation of huntingtin and formation of multivesicular bodies, changes conceivably pointing to an altered handling of huntingtin in neurons. In Huntington's disease, huntingtin also accumulates in aberrant subcellular compartments such as nuclear and neuritic aggregates co-localized with ubiquitin. The site of protein aggregation is polyglutamine-dependent, both in juvenile-onset patients having more aggregates in the nucleus and in adult-onset patients presenting more neuritic aggregates. Studies in vitro reveal that the genesis of these aggregates and cell death are tied to cleavage of mutant huntingtin. However, we found that the aggregation of mutant huntingtin can be dissociated from the extent of cell death. Thus properties of mutant huntingtin more subtle than its aggregation, such as its proteolysis and protein interactions that affect vesicle trafficking and nuclear transport, might suffice to cause neurodegeneration in the striatum and cortex. We propose that mutant huntingtin engages multiple pathogenic pathways leading to neuronal death.

Full Text

The Full Text of this article is available as a PDF (669.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aronin N., Chase K., Young C., Sapp E., Schwarz C., Matta N., Kornreich R., Landwehrmeyer B., Bird E., Beal M. F. CAG expansion affects the expression of mutant Huntingtin in the Huntington's disease brain. Neuron. 1995 Nov;15(5):1193–1201. doi: 10.1016/0896-6273(95)90106-x. [DOI] [PubMed] [Google Scholar]
  2. Aronin N., Cooper P. E., Lorenz L. J., Bird E. D., Sagar S. M., Leeman S. E., Martin J. B. Somatostatin is increased in the basal ganglia in Huntington disease. Ann Neurol. 1983 May;13(5):519–526. doi: 10.1002/ana.410130508. [DOI] [PubMed] [Google Scholar]
  3. Bao J., Sharp A. H., Wagster M. V., Becher M., Schilling G., Ross C. A., Dawson V. L., Dawson T. M. Expansion of polyglutamine repeat in huntingtin leads to abnormal protein interactions involving calmodulin. Proc Natl Acad Sci U S A. 1996 May 14;93(10):5037–5042. doi: 10.1073/pnas.93.10.5037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bates G., Lehrach H. Trinucleotide repeat expansions and human genetic disease. Bioessays. 1994 Apr;16(4):277–284. doi: 10.1002/bies.950160411. [DOI] [PubMed] [Google Scholar]
  5. Becher M. W., Kotzuk J. A., Sharp A. H., Davies S. W., Bates G. P., Price D. L., Ross C. A. Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis. 1998 Apr;4(6):387–397. doi: 10.1006/nbdi.1998.0168. [DOI] [PubMed] [Google Scholar]
  6. Bhide P. G., Day M., Sapp E., Schwarz C., Sheth A., Kim J., Young A. B., Penney J., Golden J., Aronin N. Expression of normal and mutant huntingtin in the developing brain. J Neurosci. 1996 Sep 1;16(17):5523–5535. doi: 10.1523/JNEUROSCI.16-17-05523.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Block-Galarza J., Chase K. O., Sapp E., Vaughn K. T., Vallee R. B., DiFiglia M., Aronin N. Fast transport and retrograde movement of huntingtin and HAP 1 in axons. Neuroreport. 1997 Jul 7;8(9-10):2247–2251. doi: 10.1097/00001756-199707070-00031. [DOI] [PubMed] [Google Scholar]
  8. Boutell J. M., Wood J. D., Harper P. S., Jones A. L. Huntingtin interacts with cystathionine beta-synthase. Hum Mol Genet. 1998 Mar;7(3):371–378. doi: 10.1093/hmg/7.3.371. [DOI] [PubMed] [Google Scholar]
  9. Burke J. R., Enghild J. J., Martin M. E., Jou Y. S., Myers R. M., Roses A. D., Vance J. M., Strittmatter W. J. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med. 1996 Mar;2(3):347–350. doi: 10.1038/nm0396-347. [DOI] [PubMed] [Google Scholar]
  10. Butterworth N. J., Williams L., Bullock J. Y., Love D. R., Faull R. L., Dragunow M. Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum. Neuroscience. 1998 Nov;87(1):49–53. doi: 10.1016/s0306-4522(98)00129-8. [DOI] [PubMed] [Google Scholar]
  11. Cooper J. K., Schilling G., Peters M. F., Herring W. J., Sharp A. H., Kaminsky Z., Masone J., Khan F. A., Delanoy M., Borchelt D. R. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet. 1998 May;7(5):783–790. doi: 10.1093/hmg/7.5.783. [DOI] [PubMed] [Google Scholar]
  12. Davies S. W., Turmaine M., Cozens B. A., DiFiglia M., Sharp A. H., Ross C. A., Scherzinger E., Wanker E. E., Mangiarini L., Bates G. P. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997 Aug 8;90(3):537–548. doi: 10.1016/s0092-8674(00)80513-9. [DOI] [PubMed] [Google Scholar]
  13. De Rooij K. E., Dorsman J. C., Smoor M. A., Den Dunnen J. T., Van Ommen G. J. Subcellular localization of the Huntington's disease gene product in cell lines by immunofluorescence and biochemical subcellular fractionation. Hum Mol Genet. 1996 Aug;5(8):1093–1099. doi: 10.1093/hmg/5.8.1093. [DOI] [PubMed] [Google Scholar]
  14. DiFiglia M., Sapp E., Chase K. O., Davies S. W., Bates G. P., Vonsattel J. P., Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997 Sep 26;277(5334):1990–1993. doi: 10.1126/science.277.5334.1990. [DOI] [PubMed] [Google Scholar]
  15. DiFiglia M., Sapp E., Chase K., Schwarz C., Meloni A., Young C., Martin E., Vonsattel J. P., Carraway R., Reeves S. A. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron. 1995 May;14(5):1075–1081. doi: 10.1016/0896-6273(95)90346-1. [DOI] [PubMed] [Google Scholar]
  16. Engelender S., Sharp A. H., Colomer V., Tokito M. K., Lanahan A., Worley P., Holzbaur E. L., Ross C. A. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum Mol Genet. 1997 Dec;6(13):2205–2212. doi: 10.1093/hmg/6.13.2205. [DOI] [PubMed] [Google Scholar]
  17. Faber P. W., Barnes G. T., Srinidhi J., Chen J., Gusella J. F., MacDonald M. E. Huntingtin interacts with a family of WW domain proteins. Hum Mol Genet. 1998 Sep;7(9):1463–1474. doi: 10.1093/hmg/7.9.1463. [DOI] [PubMed] [Google Scholar]
  18. Goldberg Y. P., Nicholson D. W., Rasper D. M., Kalchman M. A., Koide H. B., Graham R. K., Bromm M., Kazemi-Esfarjani P., Thornberry N. A., Vaillancourt J. P. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet. 1996 Aug;13(4):442–449. doi: 10.1038/ng0896-442. [DOI] [PubMed] [Google Scholar]
  19. Graveland G. A., Williams R. S., DiFiglia M. Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. Science. 1985 Feb 15;227(4688):770–773. doi: 10.1126/science.3155875. [DOI] [PubMed] [Google Scholar]
  20. Gusella J. F., MacDonald M. E. Huntingtin: a single bait hooks many species. Curr Opin Neurobiol. 1998 Jun;8(3):425–430. doi: 10.1016/s0959-4388(98)80071-8. [DOI] [PubMed] [Google Scholar]
  21. Gutekunst C. A., Levey A. I., Heilman C. J., Whaley W. L., Yi H., Nash N. R., Rees H. D., Madden J. J., Hersch S. M. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8710–8714. doi: 10.1073/pnas.92.19.8710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hackam A. S., Singaraja R., Wellington C. L., Metzler M., McCutcheon K., Zhang T., Kalchman M., Hayden M. R. The influence of huntingtin protein size on nuclear localization and cellular toxicity. J Cell Biol. 1998 Jun 1;141(5):1097–1105. doi: 10.1083/jcb.141.5.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hollenbeck P. J. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J Cell Biol. 1993 Apr;121(2):305–315. doi: 10.1083/jcb.121.2.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Holmberg M., Duyckaerts C., Dürr A., Cancel G., Gourfinkel-An I., Damier P., Faucheux B., Trottier Y., Hirsch E. C., Agid Y. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet. 1998 May;7(5):913–918. doi: 10.1093/hmg/7.5.913. [DOI] [PubMed] [Google Scholar]
  25. Jackson M., Gentleman S., Lennox G., Ward L., Gray T., Randall K., Morrell K., Lowe J. The cortical neuritic pathology of Huntington's disease. Neuropathol Appl Neurobiol. 1995 Feb;21(1):18–26. doi: 10.1111/j.1365-2990.1995.tb01024.x. [DOI] [PubMed] [Google Scholar]
  26. Kalchman M. A., Koide H. B., McCutcheon K., Graham R. K., Nichol K., Nishiyama K., Kazemi-Esfarjani P., Lynn F. C., Wellington C., Metzler M. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet. 1997 May;16(1):44–53. doi: 10.1038/ng0597-44. [DOI] [PubMed] [Google Scholar]
  27. Kim M., Lee H. S., LaForet G., McIntyre C., Martin E. J., Chang P., Kim T. W., Williams M., Reddy P. H., Tagle D. Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci. 1999 Feb 1;19(3):964–973. doi: 10.1523/JNEUROSCI.19-03-00964.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kim M., Velier J., Chase K., Laforet G., Kalchman M. A., Hayden M. R., Won L., Heller A., Aronin N., Difiglia M. Forskolin and dopamine D1 receptor activation increase huntingtin's association with endosomes in immortalized neuronal cells of striatal origin. Neuroscience. 1999;89(4):1159–1167. doi: 10.1016/s0306-4522(98)00400-x. [DOI] [PubMed] [Google Scholar]
  29. LaVail J. H., LaVail M. M. The retrograde intraaxonal transport of horseradish peroxidase in the chick visual system: a light and electron microscopic study. J Comp Neurol. 1974 Oct 1;157(3):303–357. doi: 10.1002/cne.901570304. [DOI] [PubMed] [Google Scholar]
  30. Li M., Miwa S., Kobayashi Y., Merry D. E., Yamamoto M., Tanaka F., Doyu M., Hashizume Y., Fischbeck K. H., Sobue G. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. 1998 Aug;44(2):249–254. doi: 10.1002/ana.410440216. [DOI] [PubMed] [Google Scholar]
  31. Li S. H., Gutekunst C. A., Hersch S. M., Li X. J. Interaction of huntingtin-associated protein with dynactin P150Glued. J Neurosci. 1998 Feb 15;18(4):1261–1269. doi: 10.1523/JNEUROSCI.18-04-01261.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Li X. J., Li S. H., Sharp A. H., Nucifora F. C., Jr, Schilling G., Lanahan A., Worley P., Snyder S. H., Ross C. A. A huntingtin-associated protein enriched in brain with implications for pathology. Nature. 1995 Nov 23;378(6555):398–402. doi: 10.1038/378398a0. [DOI] [PubMed] [Google Scholar]
  33. Lunkes A., Mandel J. L. A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum Mol Genet. 1998 Sep;7(9):1355–1361. doi: 10.1093/hmg/7.9.1355. [DOI] [PubMed] [Google Scholar]
  34. Mangiarini L., Sathasivam K., Seller M., Cozens B., Harper A., Hetherington C., Lawton M., Trottier Y., Lehrach H., Davies S. W. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996 Nov 1;87(3):493–506. doi: 10.1016/s0092-8674(00)81369-0. [DOI] [PubMed] [Google Scholar]
  35. Martindale D., Hackam A., Wieczorek A., Ellerby L., Wellington C., McCutcheon K., Singaraja R., Kazemi-Esfarjani P., Devon R., Kim S. U. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet. 1998 Feb;18(2):150–154. doi: 10.1038/ng0298-150. [DOI] [PubMed] [Google Scholar]
  36. Merry D. E., Kobayashi Y., Bailey C. K., Taye A. A., Fischbeck K. H. Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet. 1998 Apr;7(4):693–701. doi: 10.1093/hmg/7.4.693. [DOI] [PubMed] [Google Scholar]
  37. Ordway J. M., Tallaksen-Greene S., Gutekunst C. A., Bernstein E. M., Cearley J. A., Wiener H. W., Dure L. S., 4th, Lindsey R., Hersch S. M., Jope R. S. Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell. 1997 Dec 12;91(6):753–763. doi: 10.1016/s0092-8674(00)80464-x. [DOI] [PubMed] [Google Scholar]
  38. Paulson H. L., Perez M. K., Trottier Y., Trojanowski J. Q., Subramony S. H., Das S. S., Vig P., Mandel J. L., Fischbeck K. H., Pittman R. N. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997 Aug;19(2):333–344. doi: 10.1016/s0896-6273(00)80943-5. [DOI] [PubMed] [Google Scholar]
  39. Perutz M. F., Johnson T., Suzuki M., Finch J. T. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5355–5358. doi: 10.1073/pnas.91.12.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Portera-Cailliau C., Hedreen J. C., Price D. L., Koliatsos V. E. Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci. 1995 May;15(5 Pt 2):3775–3787. doi: 10.1523/JNEUROSCI.15-05-03775.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reddy P. H., Williams M., Charles V., Garrett L., Pike-Buchanan L., Whetsell W. O., Jr, Miller G., Tagle D. A. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet. 1998 Oct;20(2):198–202. doi: 10.1038/2510. [DOI] [PubMed] [Google Scholar]
  42. Sapp E., Penney J., Young A., Aronin N., Vonsattel J. P., DiFiglia M. Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J Neuropathol Exp Neurol. 1999 Feb;58(2):165–173. doi: 10.1097/00005072-199902000-00006. [DOI] [PubMed] [Google Scholar]
  43. Sapp E., Schwarz C., Chase K., Bhide P. G., Young A. B., Penney J., Vonsattel J. P., Aronin N., DiFiglia M. Huntingtin localization in brains of normal and Huntington's disease patients. Ann Neurol. 1997 Oct;42(4):604–612. doi: 10.1002/ana.410420411. [DOI] [PubMed] [Google Scholar]
  44. Saudou F., Finkbeiner S., Devys D., Greenberg M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 1998 Oct 2;95(1):55–66. doi: 10.1016/s0092-8674(00)81782-1. [DOI] [PubMed] [Google Scholar]
  45. Scherzinger E., Lurz R., Turmaine M., Mangiarini L., Hollenbach B., Hasenbank R., Bates G. P., Davies S. W., Lehrach H., Wanker E. E. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell. 1997 Aug 8;90(3):549–558. doi: 10.1016/s0092-8674(00)80514-0. [DOI] [PubMed] [Google Scholar]
  46. Sharp A. H., Loev S. J., Schilling G., Li S. H., Li X. J., Bao J., Wagster M. V., Kotzuk J. A., Steiner J. P., Lo A. Widespread expression of Huntington's disease gene (IT15) protein product. Neuron. 1995 May;14(5):1065–1074. doi: 10.1016/0896-6273(95)90345-3. [DOI] [PubMed] [Google Scholar]
  47. Sittler A., Wälter S., Wedemeyer N., Hasenbank R., Scherzinger E., Eickhoff H., Bates G. P., Lehrach H., Wanker E. E. SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell. 1998 Oct;2(4):427–436. doi: 10.1016/s1097-2765(00)80142-2. [DOI] [PubMed] [Google Scholar]
  48. Snell R. G., MacMillan J. C., Cheadle J. P., Fenton I., Lazarou L. P., Davies P., MacDonald M. E., Gusella J. F., Harper P. S., Shaw D. J. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993 Aug;4(4):393–397. doi: 10.1038/ng0893-393. [DOI] [PubMed] [Google Scholar]
  49. Trottier Y., Devys D., Imbert G., Saudou F., An I., Lutz Y., Weber C., Agid Y., Hirsch E. C., Mandel J. L. Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat Genet. 1995 May;10(1):104–110. doi: 10.1038/ng0595-104. [DOI] [PubMed] [Google Scholar]
  50. Tukamoto T., Nukina N., Ide K., Kanazawa I. Huntington's disease gene product, huntingtin, associates with microtubules in vitro. Brain Res Mol Brain Res. 1997 Nov;51(1-2):8–14. doi: 10.1016/s0169-328x(97)00205-2. [DOI] [PubMed] [Google Scholar]
  51. Velier J., Kim M., Schwarz C., Kim T. W., Sapp E., Chase K., Aronin N., DiFiglia M. Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways. Exp Neurol. 1998 Jul;152(1):34–40. doi: 10.1006/exnr.1998.6832. [DOI] [PubMed] [Google Scholar]
  52. Vonsattel J. P., DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. 1998 May;57(5):369–384. doi: 10.1097/00005072-199805000-00001. [DOI] [PubMed] [Google Scholar]
  53. Wainwright M. S., Perry B. D., Won L. A., O'Malley K. L., Wang W. Y., Ehrlich M. E., Heller A. Immortalized murine striatal neuronal cell lines expressing dopamine receptors and cholinergic properties. J Neurosci. 1995 Jan;15(1 Pt 2):676–688. doi: 10.1523/JNEUROSCI.15-01-00676.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wanker E. E., Rovira C., Scherzinger E., Hasenbank R., Wälter S., Tait D., Colicelli J., Lehrach H. HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Hum Mol Genet. 1997 Mar;6(3):487–495. doi: 10.1093/hmg/6.3.487. [DOI] [PubMed] [Google Scholar]
  55. Wexler N. S., Young A. B., Tanzi R. E., Travers H., Starosta-Rubinstein S., Penney J. B., Snodgrass S. R., Shoulson I., Gomez F., Ramos Arroyo M. A. Homozygotes for Huntington's disease. Nature. 1987 Mar 12;326(6109):194–197. doi: 10.1038/326194a0. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES