Skip to main content
SpringerLink
Log in

Neuronal Death in Huntington’s Disease: Multiple Pathways for One Issue?

  • Conference paper
Neuronal Death by Accident or by Design

Part of the book series: Research and Perspectives in Neurosciences ((NEUROSCIENCE))

Summary

Huntington’s disease (HD) is a mid-life onset neurodegenerative disorder characterized by involuntary movements (chorea), personality changes and dementia. The neuropathology of HD is a marked neuronal death in the striatum while other brain structures are selectively spared. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that is expressed as a polyglutamine repeat in the protein huntingtin. CAG expansions represent a novel type of mutation in the human genome and have also been found in several other inherited neurodegenerative disorders. The mechanisms by which mutant huntingtin induces neuronal death are not well understood. However, studies suggest a cascade of events that begins in the cytoplasm and ends with the translocation and accumulation of the mutant protein in the nucleus. During this course, mutant huntingtin might affect a wide range of intracellular systems such as vesicular transport and trafficking and the apoptotic machinery as well as transcription. Modification of one if not all of those intracellular systems could ultimately lead to the death of the striatal neurons in HD.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Albin RL, Reiner A, Anderson KD, Dure LSt, Handelin B, Balfour R, Whetsell WO Jr, Penney JB, Young AB (1992) Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann Neurol 31: 425–430

    Article  PubMed  CAS  Google Scholar 

  • Bao J, Sharp AH, Wagster MV, Becher M, Schilling G, Ross CA, Dawson VL, Dawson TM (1996) Expansion of polyglutamine repeat in huntingtin leads to abnormal protein interactions involving calmodulin. Proc Natl Acad Sci USA 93: 5037–5042

    Article  PubMed  CAS  Google Scholar 

  • Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, Ross CA (1998) 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 4: 387–397

    Article  PubMed  CAS  Google Scholar 

  • Block-Galarza J, Chase KO, Sapp E, Vaughn KT, Vallee RB, DiFiglia M, Aronin N (1997) Fast trans- port and retrograde movement of huntingtin and HAP 1 in axons. Neuroreport 8: 2247–2251

    Article  PubMed  CAS  Google Scholar 

  • Boutell JM, Thomas P, Neal JW, Weston VJ, Duce J, Harper PS, Jones AL (1999) Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Human Mol Genet 8: 1647–1655

    Article  CAS  Google Scholar 

  • Burke JR, Enghild JJ, Martin ME, Jou YS, Myers RM, Roses AD, Vance JM, Strittmatter WJ (1996) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med 2: 347–350

    Article  PubMed  CAS  Google Scholar 

  • Carmichael J, Chatellier J, Woolfson A, Milstein C, Fersht AR, Rubinsztein DC (2000) Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington’s disease. Proc Natl Acad Sci USA 97: 9701–9705

    Article  PubMed  CAS  Google Scholar 

  • Cha JH (2000) Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 23: 387–392

    Article  PubMed  CAS  Google Scholar 

  • Chai Y, Koppenhafer SL, Bonini NM, Paulson HL (1999) Analysis of the role of heat shock protein ( Hsp) molecular chaperones in polyglutamine disease. J Neurosci 19: 10338–10347

    Google Scholar 

  • Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Sian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6: 797–801

    Article  PubMed  CAS  Google Scholar 

  • Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y, Ciechanover A, Orr HT, Beaudet AL, Zoghbi HY (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24: 879–892

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Davies SW, Beardsall K, Turmaine M, DiFiglia M, Aronin N, Bates GP (1998) Are neuronal intra-nuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutaminerepeat expansions? Lancet 351: 131–133

    Article  PubMed  CAS  Google Scholar 

  • De Rooij KE, Dorsman JC, Smoor MA, Den Dunnen JT, Van Ommen GJ (1996) Subcellular localization of the Huntington’s disease gene product in cell lines by immunofluorescence and biochemical subcellular fractionation. Human Mol Genet 5: 1093–1099

    Article  Google Scholar 

  • DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA, Boyce F, Aronin N (1995) Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14: 1075–1081

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Dragatsis I, Levine MS, Zeitlin S (2000) Inactivation of hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 26: 300–306

    Article  PubMed  CAS  Google Scholar 

  • Dragunow M, Faull RL, Lawlor P, Beilharz 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. Neuroreport 6: 1053–1057

    Article  PubMed  CAS  Google Scholar 

  • Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, Ge P, Vonsattel JP, Gusella JF, Joyner AL, MacDonald ME (1995) Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science 269: 407–410

    Article  PubMed  CAS  Google Scholar 

  • Ellerby LM, Andrusiak RL, Wellington CL, Hackam AS, Propp SS, Wood JD, Sharp AH, Margolis RL, Ross CA, Salvesen GS, Hayden MR, Bredesen DE (1999a) Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. J Biol Chem 274: 8730–8736

    Article  PubMed  CAS  Google Scholar 

  • Ellerby LM, Hackam AS, Propp SS, Ellerby HM, Rabizadeh S, Cashman NR, Trifiro MA, Pinsky L, Wellington CL, Salvesen GS, Hayden MR, Bredesen DE (1999b) Kennedy’s disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J Neurochem 72: 185–195

    Article  PubMed  CAS  Google Scholar 

  • Engqvist-Goldstein AE, Kessels MM, Chopra VS, Hayden MR, Drubin DG (1999) An actin-binding protein of the Slat/Huntingtin interacting protein 1 family is a novel component of clathrincoated pits and vesicles. J Cell Biol 147: 1503–1518

    Article  PubMed  CAS  Google Scholar 

  • Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME (1998) Huntingtin interacts with a family of WW domain proteins. Human Mol Genet 7: 1463–1474

    Article  CAS  Google Scholar 

  • Faber PW, Alter JR, MacDonald ME, Hart AC (1999) Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci USA 96: 179–184

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She WC, Luchak JM, Martinez P, Turiegano E, Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr HT, Zoghbi HY, Botas J (2000) Identification of genes that modify ataxin-l-induced neurodegeneration. Nature 408: 101–106

    Article  PubMed  CAS  Google Scholar 

  • Gerber HP, Seipel K, Georgiev O, Hofferer M, Hug M, Rusconi S, Schaffner W (1994) Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 263: 808–811

    Article  PubMed  CAS  Google Scholar 

  • Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Bromm M, Kazemi-Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR (1996) Cleavage of huntingtin by apopain, a proappoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 13: 442–449

    Article  PubMed  CAS  Google Scholar 

  • Graveland GA, Williams RS, DiFiglia M (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science 227: 770–773

    Article  PubMed  CAS  Google Scholar 

  • Group THsDCR (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72: 971–983

    Article  Google Scholar 

  • Gusella JF, MacDonald ME (1995) Huntington’s disease. Sem Cell Biol 6: 21–28

    Article  CAS  Google Scholar 

  • Gusella JF, MacDonald ME (1998) Huntingtin: a single bait hooks many species. Curr Opin Neurobiol 8: 425–430

    Article  PubMed  CAS  Google Scholar 

  • Gutekunst CA, Levey AI, Heilman CJ, Whaley WL, Yi H, Nash NR, Rees HD, Madden JJ, Hersch SM (1995) Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci USA 92: 8710–8714

    Article  PubMed  CAS  Google Scholar 

  • Gutekunst CA, Li SH, Yi H, Ferrante RJ, Li XJ, Hersch SM (1998) The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human. J Neurosci 18: 7674–7686

    PubMed  CAS  Google Scholar 

  • Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, Rye D, Ferrante RJ, Hersch SM, Li XJ (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 19: 2522–2534

    PubMed  CAS  Google Scholar 

  • Hackam AS, Yassa AS, Singaraja R, Metzler M, Gutekunst CA, Gan L, Warby S, Wellington CL, Vaillancourt J, Chen N, Gervais FG, Raymond L, Nicholson DW, Hayden MR (2000) Huntingtin interacting protein 1 (HIP-1) induces apoptosis via a novel caspase-dependent death effector domain. J Biol Chem 275: 41299–41308

    Article  PubMed  CAS  Google Scholar 

  • Hedreen JC, Folstein SE (1995) Early loss of neostriatal striosome neurons in Huntington’s disease. J Neuropathol Exp Neurol 54: 105–120

    Article  PubMed  CAS  Google Scholar 

  • 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 hungtingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23: 181–192

    Article  PubMed  CAS  Google Scholar 

  • Huang CC, Faber PW, Persichetti F, Mittal V, Vonsattel JP, MacDonald ME, Gusella JF (1998) Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat Cell Mol Genet 24: 217–233

    Article  PubMed  CAS  Google Scholar 

  • Jackson GR, Salecker I, Dong X, Yao X, Arnheim N, Faber PW, MacDonald ME, Zipursky SL (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21: 633–642

    Article  PubMed  CAS  Google Scholar 

  • Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR (1996) Hungtingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme. J Biol Chem 271: 19385–19394

    Article  PubMed  CAS  Google Scholar 

  • 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 homologue of S. cerevisiae Sla2p, interacts with membrane-associated hunting-tin in the brain. Nat Genet 16: 44–53

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kazemi-Esfarjani P, Benzer S (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287: 1837–1840

    Article  PubMed  CAS  Google Scholar 

  • Kegel KB, Kim M, Sapp E, McIntyre C, Castano JG, Aronin N, DiFiglia M (2000) Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy [In Process Citation]. J Neurosci 20: 7268–7278

    PubMed  CAS  Google Scholar 

  • 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 (1999a) Mutant huntingtin expression in clonal striated cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci 19: 964–973

    PubMed  CAS  Google Scholar 

  • Kim M, Velier J, Chase K, Laforet G, Kalchman MA, Hayden MR, Won L, Heller A, Aronin N, Di-Figlia M (1999b) Forskolin and dopamine D1 receptor activation increase huntingtin’s association with endosomes in immortalized neuronal cells of striatal origin. Neuroscience 89: 1159–1167

    Article  PubMed  CAS  Google Scholar 

  • 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 polyglutamine-induced disease in SCA1 trans-genic mice. Cell 95: 41–53

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi Y, Kume A, Li M, Doyu M, Hata M, Ohtsuka K, Sobue G (2000) Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J Biol Chem 275: 87728778

    Google Scholar 

  • Kouroku Y, Fujita E, Jimbo A, Mukasa T, Tsuru T, Momoi MY, Momoi T (2000) Localization of active form of caspase-8 in mouse L929 cells induced by TNF treatment and polyglutamine aggregates. Biochem Biophys Res Commun 270: 972–977

    Article  PubMed  CAS  Google Scholar 

  • Kuemmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, Beal MF, Hersch SM, Ferrante RJ (1999) Huntington aggregates may not predict neuronal death in Huntington’s disease. Ann Neurol 46: 842–849

    Article  PubMed  CAS  Google Scholar 

  • Li H, Li SH, Johnston H, Shelbourne PF, Li XJ (2000) Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 25: 385–389

    Article  PubMed  CAS  Google Scholar 

  • Li SH, Gutekunst CA, Hersch SM, Li XJ (1998) Interaction of huntingtin-associated protein with dynactin P15OGlued. J Neurosci 18: 1261–1269

    PubMed  CAS  Google Scholar 

  • Li XJ (2000) The early cellular pathology of Huntington’s disease. Mol Neurobiol 20: 111–124

    Article  CAS  Google Scholar 

  • Li X], Li SH, Sharp AH, Nucifora FC Jr, Schilling G, Lanahan A, Worley P, Snyder SH, Ross CA (1995) A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378: 398–402

    Article  Google Scholar 

  • Liu YF (1998) Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J Biol Chem 273: 28873–28877

    Article  PubMed  CAS  Google Scholar 

  • Liu YF, Deth RC, Devys D (1997) SH3 domain-dependent association of huntingtin with epider-mal growth factor receptor signaling complexes. J Biol Chem 272: 8121–8124

    Article  PubMed  CAS  Google Scholar 

  • Liu YF, Dorow D, Marshall J (2000) Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin. J Biol Chem 275: 19035–19040

    Article  PubMed  CAS  Google Scholar 

  • Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS, Penney EB, Schilling G, Ross CA, Borchelt DR, Tapscott SJ, Young AB, Cha JH, Olson JM (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Human Mol Genet 9: 1259–1271

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Martin EJ, Kim M, Velier J, Sapp E, Lee HS, Laforet G, Won L, Chase K, Bhide PG, Heller A, Aronin N, DiFiglia M (1999) Analysis of Huntingtin-associated protein 1 in mouse brain and immortalized striatal neurons. J Comp Neurol 403: 421–430

    Article  PubMed  CAS  Google Scholar 

  • Martin JB, Gusella JF (1986) Huntington’s disease. Pathogenesis and management. New Engl J Med 315: 1267–1276

    Google Scholar 

  • Martindale D, Hackam A, Wieczorek A, Ellerby L, Wellington C, McCutcheon K, Singaraja R, Kazemi-Esfarjani P, Devon R, Kim SU, Bredesen DE, Tufaro F, Hayden MR (1998) Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet 18: 150–154

    Article  PubMed  CAS  Google Scholar 

  • McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G, Fischbeck KH (2000) CREB-binding protein sequestration by expanded polyglutamine. Human Mol Genet 9: 2197–2202

    Article  CAS  Google Scholar 

  • Miyashita T, Okamura-Oho Y, Mito Y, Nagafuchi S, Yamada M (1997) Dentatorubral pallidoluysian atrophy (DRPLA) protein is cleaved by caspase-3 during apoptosis. J Biol Chem 272: 2923829243

    Google Scholar 

  • 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 Commun 257: 724–730

    Article  PubMed  CAS  Google Scholar 

  • Muchowski PJ, Schaffar G, Sittler A, Wanker EE, Hayer-Hartl MK, Hartl FU (2000) Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like firbrils. Proc Natl Acad Sci USA 97: 7841–7846

    Article  PubMed  CAS  Google Scholar 

  • Nasir J, Floresco SB, O’Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR (1995) Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81: 811–823

    Article  PubMed  CAS  Google Scholar 

  • Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, 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: 263–267

    Article  PubMed  CAS  Google Scholar 

  • Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE (1995) Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci 15: 3775–3787

    PubMed  CAS  Google Scholar 

  • Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO Jr, Miller G, Tagle DA (1998) Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated fill-length HD cDNA. Nat Genet 20: 198–202

    Article  PubMed  CAS  Google Scholar 

  • Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB (1988) Differential loss of striatal projection neurons in Huntington’s disease. Proc Natl Acad Sci USA 85: 5733–5737

    Article  PubMed  CAS  Google Scholar 

  • Rigamonti D, Bauer JH, De-Fraja C, Conti L, Sipione S, Sciorati C, Clementi E, Hackam A, Hayden MR, Li Y, Copper JK, Ross CA, Govoni S, Vincenz C, Cattaneo E (2000) Wild-type huntington protects form apoptosis upstream of caspase-3. J Neurosci 20: 3705–3713

    PubMed  CAS  Google Scholar 

  • Ross CA (1997) Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 19: 1147–1150

    Article  PubMed  CAS  Google Scholar 

  • Sanchez I, Xu C-J, Juo P, Kakizaka A, Blenis J, Yuan J (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22: 623–633

    Article  PubMed  CAS  Google Scholar 

  • Sapp E, Ge P, Aizawa H, Bird E, Penney J, Young AB, Vonsattel JP, DiFiglia M (1995) Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington’s disease using high resolution image analysis. Neurosci 64: 397–404

    Article  CAS  Google Scholar 

  • Sapp E, Penney J, Young A, Aronin N, Vonsattel JP, DiFiglia M (1999) Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J Neuropathol Exp Neurol 58: 165–173

    Article  PubMed  CAS  Google Scholar 

  • Satyal SH, Schmidt E, Kitagawa K, Sondheimer N, Lindquist S, Kramer JM, Morimoto RI (2000) Polyglutamine aggregates alter protein folding homeostosis in Caenorhabditis elegans. Proc Natl Acad Sic USA 97: 5750–5755

    Article  CAS  Google Scholar 

  • Saudou F, Devys D, Trottier Y, Imbert G, Stoeckel ME, Brice A, Mandel JL (1996) Polyglutamine expansions and neurodegenerative diseases. In: Cold Spring Harbor Laboratory (eds) Cold Spring Habor Symposia Quantitative Biology 61, pp 639–647

    Google Scholar 

  • Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptotsis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55–66

    Article  PubMed  CAS  Google Scholar 

  • Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler JF Jr, Greenamyre JT, Synder SH, Ross CA (1999) Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat Med 5: 1194–1198

    Article  PubMed  CAS  Google Scholar 

  • 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. Human Mol Genet 8: 397–404

    Article  CAS  Google Scholar 

  • Sharp AH, Ross CA (1996) Neurobiology of Huntington’s disease. Neurobiol Dis 3: 3–15

    Article  PubMed  CAS  Google Scholar 

  • Sharp AH, Loev SJ, Schilling G, Li SH, Li XJ, Bao J, Wagster MV, Kotzuk JA, Steiner JP, Lo A, Hedreen J, Sisodia S, Snyder SH, Dawson TM, Ryugo DK, Ross CA (1995) Widespread expression of Huntington’s disease gene (IT15) protein product. Neuron 14: 1065–1074

    Article  PubMed  CAS  Google Scholar 

  • Shelbourne PF, Killeen N, Hevner RF, Johnston HM, Tecott L, Lewandoski M, Ennis M, Ramirez L, Li Z, Iannicola C, Littman DR, Myers RM (1999) A Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Human Mol Genet 8: 763–774

    Article  CAS  Google Scholar 

  • Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S, Kimura T, Koide R, Nozaki K, Sano Y, Ishiguro H, Sakoe K, Ooshima T, Sato A, Ikeuchi T, Oyake M, Sato T, Aoyagi Y, Hozumi I, Nagatsu T, Takiyama Y, Nishizawa M, Goto J, Kanazawa I, Davidson I, Tanese N (2000) Expanded polyglutamine stetches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26: 29–36

    Article  PubMed  CAS  Google Scholar 

  • Sittler A, Walter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates GP, Lehrach H, Wanker EE (1998) SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell 2: 427–436

    Article  PubMed  CAS  Google Scholar 

  • Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Si USA 97: 6763–6768

    Article  CAS  Google Scholar 

  • 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. Human Mol Genet 8: 731–741

    Article  CAS  Google Scholar 

  • 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

    Google Scholar 

  • Trottier Y, Devys D, Imbert G, Saudou F, An I, Lutz Y, Weber C, Agid Y, Hirsch EC, Mandel JL (1995 a) Cellular localization of the Huntington’s disease protein and discrimination of the normal and mutated form. Nat Genet 10: 104–110

    Google Scholar 

  • Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L, Agid Y, Brice A, Mandel J-L (1995b) Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 378: 403–406

    Article  PubMed  CAS  Google Scholar 

  • Tukamoto T, Nukine N, Ide K, Kanazawa J (1997) Huntington’s disease gene product, huntingtin, associates with microtubules in vitro. Brain Res Mol Brain Res 51: 8–14

    Article  PubMed  CAS  Google Scholar 

  • Turmaine M, Raza A, Mahal A, Mangiarini L, Bates GP, Davies SW (2000) Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci USA 97: 8093–8097

    Article  PubMed  CAS  Google Scholar 

  • Velier J, Kim M, Schwarz C, Kim TW, Sapp E, Chase K, Aronin N, DiFiglia M (1998) Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways. Exp Neurol 152: 34–40

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Wang GH, Mitsui K, Kotliarova S, Yamashita A, Nagao Y, Tokuhiro S, Iwatsubo T, Kanazawa I, Nukina N (1999) Caspase activation during apoptotic cell death induced by expanded polyglutamine in N2a cells. Neuroreport 10: 2435–2438

    Article  PubMed  CAS  Google Scholar 

  • Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, Tait D, Colicelli J, Lehrach H (1997) HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Human Mol Genet 6: 487–495

    Article  CAS  Google Scholar 

  • Warrick JM, Paulson HL, Gray-Board GL, 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

    Article  Google Scholar 

  • Wellington CL, Hayden MR (2000) Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches. Clin Genet 57: 1–10

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Wellington CL, Singaraja R, Ellerby L, Savill J, Roy S, Leavitt B, Cattaneo E, Hackam A, Sharp A, Thornberry N, Nicholson DW, Bredesen DE, Hyden MR (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J Biol Chem 275: 19831–19838

    Article  PubMed  CAS  Google Scholar 

  • White JK, Auerbach W, Duyao MP, Vonsattel JP, Gusella JF, Joyner AL, MacDonald ME (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet 17: 404–410

    Article  PubMed  CAS  Google Scholar 

  • Wyttenbach A, Carmichael J, Swartz J, Furlong RA, Narain Y, Rankin J, Rubinsztein DC (2000) Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease. Proc Natl Acad Sci USA 97: 2898–2903

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101: 57–66

    Article  PubMed  CAS  Google Scholar 

  • Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 11: 155–163

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. S. Humbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Saudou
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. INSERM U.382 — IBDM (CNRS — INSERM — Univ. Méditerranée), Campus de Luminy, Case 907, 13288, Marseille Cedex 09, France

    Christopher E. Henderson Ph. D.

  2. Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, 92121, San Diego, CA, USA

    Douglas R. Green Ph. D.

  3. Institut des Neurosciences, UMR 7624, CNRS et Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005, Paris, France

    Jean Mariani Ph. D.

  4. Pour la Recherche Thérapeutique, Fondation IPSEN, 24, rue Erlanger, 75781, Paris Cedex 16, France

    Yves Christen Ph. D.

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Humbert, S., Saudou, F. (2001). Neuronal Death in Huntington’s Disease: Multiple Pathways for One Issue?. In: Henderson, C.E., Green, D.R., Mariani, J., Christen, Y. (eds) Neuronal Death by Accident or by Design. Research and Perspectives in Neurosciences. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04333-2_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-04333-2_11

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-07517-9

  • Online ISBN: 978-3-662-04333-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation