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Philos Trans R Soc Lond B Biol Sci. 1999 June 29; 354(1386): 995–1003.
PMCID: PMC1692615

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


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.

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Selected References

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  • Aronin N, Cooper PE, Lorenz LJ, Bird ED, Sagar SM, Leeman SE, Martin JB. Somatostatin is increased in the basal ganglia in Huntington disease. Ann Neurol. 1983 May;13(5):519–526. [PubMed]
  • Aronin N, Chase K, Young C, Sapp E, Schwarz C, Matta N, Kornreich R, Landwehrmeyer B, Bird E, Beal MF, et al. CAG expansion affects the expression of mutant Huntingtin in the Huntington's disease brain. Neuron. 1995 Nov;15(5):1193–1201. [PubMed]
  • Bao J, Sharp AH, Wagster MV, Becher M, Schilling G, Ross CA, Dawson VL, Dawson TM. 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. [PubMed]
  • Bates G, Lehrach H. Trinucleotide repeat expansions and human genetic disease. Bioessays. 1994 Apr;16(4):277–284. [PubMed]
  • Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, Ross CA. 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. [PubMed]
  • Bhide PG, Day M, Sapp E, Schwarz C, Sheth A, Kim J, Young AB, Penney J, Golden J, Aronin N, et al. Expression of normal and mutant huntingtin in the developing brain. J Neurosci. 1996 Sep 1;16(17):5523–5535. [PubMed]
  • Block-Galarza J, Chase KO, Sapp E, Vaughn KT, Vallee RB, 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. [PubMed]
  • Boutell JM, Wood JD, Harper PS, Jones AL. Huntingtin interacts with cystathionine beta-synthase. Hum Mol Genet. 1998 Mar;7(3):371–378. [PubMed]
  • Burke JR, Enghild JJ, Martin ME, Jou YS, Myers RM, Roses AD, Vance JM, Strittmatter WJ. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med. 1996 Mar;2(3):347–350. [PubMed]
  • Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RL, 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. [PubMed]
  • Cooper JK, Schilling G, Peters MF, Herring WJ, Sharp AH, Kaminsky Z, Masone J, Khan FA, Delanoy M, Borchelt DR, et al. 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. [PubMed]
  • Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997 Aug 8;90(3):537–548. [PubMed]
  • De Rooij KE, Dorsman JC, Smoor MA, Den Dunnen JT, Van Ommen GJ. 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. [PubMed]
  • DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA, et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron. 1995 May;14(5):1075–1081. [PubMed]
  • DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997 Sep 26;277(5334):1990–1993. [PubMed]
  • Engelender S, Sharp AH, Colomer V, Tokito MK, Lanahan A, Worley P, Holzbaur EL, Ross CA. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum Mol Genet. 1997 Dec;6(13):2205–2212. [PubMed]
  • Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME. Huntingtin interacts with a family of WW domain proteins. Hum Mol Genet. 1998 Sep;7(9):1463–1474. [PubMed]
  • Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Bromm M, Kazemi-Esfarjani P, Thornberry NA, Vaillancourt JP, et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet. 1996 Aug;13(4):442–449. [PubMed]
  • Graveland GA, Williams RS, DiFiglia M. Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. Science. 1985 Feb 15;227(4688):770–773. [PubMed]
  • Gusella JF, MacDonald ME. Huntingtin: a single bait hooks many species. Curr Opin Neurobiol. 1998 Jun;8(3):425–430. [PubMed]
  • Gutekunst CA, Levey AI, Heilman CJ, Whaley WL, Yi H, Nash NR, Rees HD, Madden JJ, Hersch SM. 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. [PubMed]
  • Hackam AS, Singaraja R, Wellington CL, Metzler M, McCutcheon K, Zhang T, Kalchman M, Hayden MR. The influence of huntingtin protein size on nuclear localization and cellular toxicity. J Cell Biol. 1998 Jun 1;141(5):1097–1105. [PMC free article] [PubMed]
  • Hollenbeck PJ. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J Cell Biol. 1993 Apr;121(2):305–315. [PMC free article] [PubMed]
  • Holmberg M, Duyckaerts C, Dürr A, Cancel G, Gourfinkel-An I, Damier P, Faucheux B, Trottier Y, Hirsch EC, Agid Y, et al. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet. 1998 May;7(5):913–918. [PubMed]
  • 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. [PubMed]
  • Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, Kazemi-Esfarjani P, Lynn FC, Wellington C, Metzler M, et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet. 1997 May;16(1):44–53. [PubMed]
  • Kim M, Lee HS, LaForet G, McIntyre C, Martin EJ, Chang P, Kim TW, Williams M, Reddy PH, Tagle D, et al. 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. [PubMed]
  • Kim M, Velier J, Chase K, Laforet G, Kalchman MA, Hayden MR, 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. [PubMed]
  • LaVail JH, LaVail MM. 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. [PubMed]
  • Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. 1998 Aug;44(2):249–254. [PubMed]
  • Li SH, Gutekunst CA, Hersch SM, Li XJ. Interaction of huntingtin-associated protein with dynactin P150Glued. J Neurosci. 1998 Feb 15;18(4):1261–1269. [PubMed]
  • Li XJ, Li SH, Sharp AH, Nucifora FC, Jr, Schilling G, Lanahan A, Worley P, Snyder SH, Ross CA. A huntingtin-associated protein enriched in brain with implications for pathology. Nature. 1995 Nov 23;378(6555):398–402. [PubMed]
  • Lunkes A, Mandel JL. A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum Mol Genet. 1998 Sep;7(9):1355–1361. [PubMed]
  • Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, et al. 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. [PubMed]
  • Martindale D, Hackam A, Wieczorek A, Ellerby L, Wellington C, McCutcheon K, Singaraja R, Kazemi-Esfarjani P, Devon R, Kim SU, et al. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet. 1998 Feb;18(2):150–154. [PubMed]
  • Merry DE, Kobayashi Y, Bailey CK, Taye AA, Fischbeck KH. Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet. 1998 Apr;7(4):693–701. [PubMed]
  • Ordway JM, Tallaksen-Greene S, Gutekunst CA, Bernstein EM, Cearley JA, Wiener HW, Dure LS, 4th, Lindsey R, Hersch SM, Jope RS, et al. 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. [PubMed]
  • Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997 Aug;19(2):333–344. [PubMed]
  • Perutz MF, Johnson T, Suzuki M, Finch JT. 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. [PubMed]
  • Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE. Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci. 1995 May;15(5 Pt 2):3775–3787. [PubMed]
  • Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO, Jr, Miller G, Tagle DA. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet. 1998 Oct;20(2):198–202. [PubMed]
  • Sapp E, Schwarz C, Chase K, Bhide PG, Young AB, Penney J, Vonsattel JP, Aronin N, DiFiglia M. Huntingtin localization in brains of normal and Huntington's disease patients. Ann Neurol. 1997 Oct;42(4):604–612. [PubMed]
  • Sapp E, Penney J, Young A, Aronin N, Vonsattel JP, 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. [PubMed]
  • Saudou F, Finkbeiner S, Devys D, Greenberg ME. 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. [PubMed]
  • Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, Bates GP, Davies SW, Lehrach H, Wanker EE. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell. 1997 Aug 8;90(3):549–558. [PubMed]
  • Sharp AH, Loev SJ, Schilling G, Li SH, Li XJ, Bao J, Wagster MV, Kotzuk JA, Steiner JP, Lo A, et al. Widespread expression of Huntington's disease gene (IT15) protein product. Neuron. 1995 May;14(5):1065–1074. [PubMed]
  • Sittler A, Wälter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates GP, Lehrach H, Wanker EE. 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. [PubMed]
  • Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P, MacDonald ME, Gusella JF, Harper PS, Shaw DJ. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993 Aug;4(4):393–397. [PubMed]
  • Trottier Y, Devys D, Imbert G, Saudou F, An I, Lutz Y, Weber C, Agid Y, Hirsch EC, Mandel JL. Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat Genet. 1995 May;10(1):104–110. [PubMed]
  • 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. [PubMed]
  • Velier J, Kim M, Schwarz C, Kim TW, 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. [PubMed]
  • Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. 1998 May;57(5):369–384. [PubMed]
  • Wainwright MS, Perry BD, Won LA, O'Malley KL, Wang WY, Ehrlich ME, Heller A. Immortalized murine striatal neuronal cell lines expressing dopamine receptors and cholinergic properties. J Neurosci. 1995 Jan;15(1 Pt 2):676–688. [PubMed]
  • Wanker EE, 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. [PubMed]
  • Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA, et al. Homozygotes for Huntington's disease. Nature. 1987 Mar 12;326(6109):194–197. [PubMed]

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