Polyglutamine Aggregation in Huntington and Related Diseases

  • Saskia Polling
  • Andrew F. Hill
  • Danny M. HattersEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


Polyglutamine(polyQ)-expansions in differentproteins cause nine neurodegenerative diseases. While polyQ aggregation is a key pathological hallmark of these diseases, how aggregation relates to pathogenesis remains contentious. In this chapter, we review what is known about the aggregation process and how cells respond and interact with the polyQ-expanded proteins. We cover detailed biophysical and structural studies to uncover the intrinsic features of polyQ aggregates and concomitant effects in the cellular environment. We also examine the functional consequences of polyQ aggregation and how cells may attempt to intervene and guide the aggregation process.


Huntington Disease Myotonic Dystrophy Mutant Huntingtin Polyglutamine Disease Tandem Repeat Polymorphism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s disease collaborative research group. Cell 1993; 72(6):971–983.CrossRefGoogle Scholar
  2. 2.
    Orr HT, Chung MY, Banfi S et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993; 4(3):221–226.PubMedCrossRefGoogle Scholar
  3. 3.
    Imbert G, Saudou F, Yvert G et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 1996; 14(3):285–291.PubMedCrossRefGoogle Scholar
  4. 4.
    Sanpei K, Takano H, Igarashi S et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 1996; 14(3):277–284.PubMedCrossRefGoogle Scholar
  5. 5.
    Kawaguchi Y, Okamoto T, Taniwaki M et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994; 8(3):221–228.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhuchenko O, Bailey J, Bonnen P et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 1997; 15(1):62–69.PubMedCrossRefGoogle Scholar
  7. 7.
    David G, Abbas N, Stevanin G et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997; 17(1):65–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Nakamura K, Jeong SY, Uchihara T et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 2001; 10(14):1441–1448.PubMedCrossRefGoogle Scholar
  9. 9.
    Andrew SE, Goldberg YP, Kremer B et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 1993; 4(4):398–403.PubMedCrossRefGoogle Scholar
  10. 10.
    La Spada AR, Wilson EM, Lubahn DB et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352(6330):77–79.CrossRefPubMedGoogle Scholar
  11. 11.
    Koide R, Ikeuchi T, Onodera O et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 1994; 6(1):9–13.PubMedCrossRefGoogle Scholar
  12. 12.
    Nagafuchi S, Yanagisawa H, Ohsaki E et al. Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA). Nat Genet 1994; 8(2):177–182.PubMedCrossRefGoogle Scholar
  13. 13.
    Koshy BT, Zoghbi HY. The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. Brain Pathol 1997; 7(3):927–942.PubMedCrossRefGoogle Scholar
  14. 14.
    Scherzinger E, Lurz R, Turmaine M et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90(3):549–558.PubMedCrossRefGoogle Scholar
  15. 15.
    Scherzinger E, Sittler A, Schweiger K et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc Natl Acad Sci U S A 1999; 96(8):4604–4609.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Caputo CB, Fraser PE, Sobel IE et al. Amyloid-like properties of a synthetic peptide corresponding to the carboxy terminus of beta-amyloid protein precursor. Arch Biochem Biophys 1992; 292(1):199–205.PubMedCrossRefGoogle Scholar
  17. 17.
    Prusiner SB, McKinley MP, Bowman KA et al. Scrapie prions aggregate to form amyloid-like bireringent rods. Cell 1983; 35(2 Pt l):349–358.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Huang CC, Faber PW, Persichetti F et al. Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat Cell Mol Genet 1998; 24(4):217–233.PubMedCrossRefGoogle Scholar
  19. 19.
    Ferrone F. Analysis of protein aggregation kinetics. Methods Enzymol 1999; 309:256–274.PubMedCrossRefGoogle Scholar
  20. 20.
    Berthelier V, Hamilton JB, Chen S et al. A microtiter plate assay for polyglutamine aggregate extension. Anal Biochem 2001; 295(2):227–236.PubMedCrossRefGoogle Scholar
  21. 21.
    Esler WP, Stimson ER, Jennings JM et al. Alzheimer’s disease amyloid propagation by atemplate-dependent dock-lock mechanism. Biochemistry 2000; 39(21):6288–6295.PubMedCrossRefGoogle Scholar
  22. 22.
    Jarrett JT, Lansbury PT Jr. Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 1993; 73(6): 1055–1058.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen S, Ferrone FA, Wetzel R. Huntington’s disease age-of-onset linked to polyglutamine aggregation nucleation. Proc Natl Acad Sci U S A 2002; 99(18):11884–11889.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Bernacki JP, Murphy RM. Model discrimination and mechanistic interpretation of kinetic data in protein aggregation studies. Biophys J 2009; 96(7):2871–2887.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Walters RH, Murphy RM. Examining polyglutamine peptide length: a connection between collapsed conformations and increased aggregation. J Mol Biol 2009; 393(4):978–992.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Lee CC, Walters RH, Murphy RM. Reconsidering the mechanism of polyglutamine peptide aggregation. Biochemistry 2007; 46(44):12810–12820.PubMedCrossRefGoogle Scholar
  27. 27.
    Legleiter J, Mitchell E, Lotz GP et al. Mutant huntingtin fragments form oligomers in a polyglutamine length-dependent manner in vitro and in vivo. J Biol Chem 2010; 285(19):14777–14790.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wacker JL, Zareie MH, Fong H et al. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat Struct Mol Biol 2004; 11(12): 1215–1222.PubMedCrossRefGoogle Scholar
  29. 29.
    Bhattacharyya AM, Thakur AK, Wetzel R. polyglutamine aggregation nucleation: thermodynamics of a highly unfavorable protein folding reaction. Proc Natl Acad Sci U S A 2005; 102(43): 15400–15405.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Dougan L, Li J, Badilla CL et al. Single homopolypeptide chains collapse into mechanically rigid conformations. Proc Natl Acad Sci U S A 2009; 106(31): 12605–12610.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Wang X, Vitalis A, Wyczalkowski MA et al. Characterizing the conformational ensemble of monomeric polyglutamine. Proteins 2006; 63(2):297–311.PubMedCrossRefGoogle Scholar
  32. 32.
    Crick SL, Jayaraman M, Frieden C et al. Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions. Proc Natl Acad Sci U S A 2006; 103(45):16764–16769.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Altschuler EL, Hud NV, Mazrimas JA et al. Random coil conformation for extended polyglutamine stretches in aqueous soluble monomeric peptides. J Pept Res 1997; 50(1):73–75.PubMedCrossRefGoogle Scholar
  34. 34.
    Chen S, Berthelier V, Yang W et al. Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J Mol Biol 2001; 311(1): 173–182.PubMedCrossRefGoogle Scholar
  35. 35.
    Masino L, Kelly G, Leonard K et al. Solution structure of polyglutamine tracts in GST-polyglutamine fusion proteins. FEBS Lett 2002; 513(2–3):267–272.PubMedCrossRefGoogle Scholar
  36. 36.
    Vitalis A, Wang X, Pappu RV. Atomistic simulations of the effects of polyglutamine chain length and solvent quality on conformational equilibria and spontaneous homodimerization. JMol Biol 2008; 384(1):279–297.CrossRefGoogle Scholar
  37. 37.
    Pappu RV, Wang X, Vitalis A et al. A polymer physics perspective on driving forces and mechanisms for protein aggregation. Arch Biochem Biophys 2008; 469(1):132–141.PubMedCrossRefGoogle Scholar
  38. 38.
    Venkatraman P, Wetzel R, Tanaka M et al. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell 2004; 14(1):95–104.PubMedCrossRefGoogle Scholar
  39. 39.
    Poirier MA, Li H, Macosko J et al. Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrilization. J Biol Chem 2002; 277(43):41032–41037.PubMedCrossRefGoogle Scholar
  40. 40.
    Chen S, Berthelier V, Hamilton JB et al. Amyloid-like features of polyglutamine aggregates and their assembly kinetics. Biochemistry 2002; 41(23):7391–7399.PubMedCrossRefGoogle Scholar
  41. 41.
    Vitalis A, Lyle N, Pappu RV. Thermodynamics of beta-sheet formation in polyglutamine. Biophys J 2009; 97(1):303–311.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Bhattacharyya A, Thakur AK, Chellgren VM et al. Oligoproline effects on polyglutamine conformation and aggregation. J Mol Biol 2006; 355(3):524–535.PubMedCrossRefGoogle Scholar
  43. 43.
    Nekooki-Machida Y, Kurosawa M, Nukina N et al. Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proc Natl Acad Sci U S A 2009; 106(24):9679–9684.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Bevivino AE, Loll PJ. An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel beta-fibrils. Proc Natl Acad Sci U S A 2001; 98(21):11955–11960.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Perutz MF, Finch JT, Berriman J et al. Amyloid fibers are water-filled nanotubes. Proc Natl Acad Sci U S A 2002;99(8):5591–5595.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Singer SJ, Dewji NN. Evidence that Perutz’s double-beta-stranded subunit structure for beta-amyloids also applies to theirchannel-forming structures inmembranes. Proc Natl Acad Sci U S A 2006; 103(5): 1546–1550.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Perutz MF, Johnson T, Suzuki M et al. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A 1994; 91(12):5355–5358.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Sharma D, Shinchuk LM, Inouye H et al. Polyglutamine homopolymers having 8–45 residues form slablike beta-crystallite assemblies. Proteins 2005; 61(2):398–411.PubMedCrossRefGoogle Scholar
  49. 49.
    Tanaka M, Morishima I, Akagi T et al. Intra-and intermolecular beta-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for polyglutamine diseases. J Biol Chem 2001; 276(48):45470–45475.PubMedCrossRefGoogle Scholar
  50. 50.
    Sikorski P, Atkins E. New model for crystalline polyglutamine assemblies and their connection with amyloid fibrils. Biomacromolecules 2005; 6(1):425–432.PubMedCrossRefGoogle Scholar
  51. 51.
    Thakur AK, Wetzel R. Mutational analysis of the structural organization of polyglutamine aggregates. Proc Natl Acad Sci U S A 2002; 99(26):17014–17019.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Makin OS, Atkins E, Sikorski P et al. Molecular basis for amyloid fibril formation and stability. Proc Natl Acad Sci U S A 2005; 102(2):315–320.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    DiFiglia M, Sapp E, Chase KO et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997; 277(5334): 1990–1993.CrossRefGoogle Scholar
  54. 54.
    Davies SW, Turmaine M, Cozens BA et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90(3):537–548.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Lunkes A, Trottier Y, Mandel JL. Pathological mechanisms inHuntington’s disease and other polyglutamine expansion diseases. Essays Biochem 1998; 33:149–163.PubMedCrossRefGoogle Scholar
  56. 56.
    Olshina MA, Angley LM, Ramdzan YM et al. Tracking mutant huntingtin aggre gation kinetics in cells reveals three major populations that include an invariant oligomer pool. J Biol Chem 2010; 285(28):21807–21816.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ramdzan YM, Nisbet RM, Miller J et al. Conformation sensors that distinguish monomeric proteins from oligomers in live cells. Chem Biol 2010; 17(4):371–379.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ossato G, Digman MA, Aiken C et al. A two-step path to inclusion formation of huntingtin peptides revealed by number and brightness analysis. Biophys J 2010; 98(12):3078–3085.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Muchowski PJ, Ning K, D’Souza-Schorey C et al. Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment. Proc Natl Acad Sci U S A 2002; 99(2):727–732.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Taylor JP, Tanaka F, Robitschek J et al. Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet 2003; 12(7):749–757.PubMedCrossRefGoogle Scholar
  61. 61.
    Mitra S, Tsvetkov AS, Finkbeiner S. Single neuron ubiquitin-proteasome dynamics accompanying inclusion body formation in Huntington disease. J Biol Chem 2009; 284(7):4398–4403.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Ortega Z, Diaz-Hernandez M, Maynard CJ et al. Acute polyglutamine expression in inducible mouse model unravels ubiquitin/proteasome system impairment and permanent recovery attributable to aggregate formation. J Neurosci 2010; 30(10):3675–3688.PubMedCrossRefGoogle Scholar
  63. 63.
    Arrasate M, Mitra S, Schweitzer ES et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004; 431(7010):805–810.PubMedCrossRefGoogle Scholar
  64. 64.
    Kaganovich D, Kopito R, Frydman J. Misfolded proteins partition between two distinct quality control compartments. Nature 2008; 454(7208):1088–1095.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Johnston JA, Ming ME, Kopito RR. Cytoplasmic dynein/dynactin mediates the assembly of aggresomes. Cell Motil Cytoskeleton 2002; 53(1):26–38.PubMedCrossRefGoogle Scholar
  66. 66.
    Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins. J Cell Biol 1998; 143(7):1883–1898.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 2000; 10(12):524–530.PubMedCrossRefGoogle Scholar
  68. 68.
    Garcia-Mata R, Bebok Z, Sorscher EJ et al. Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J Cell Biol 1999; 146(6):1239–1254.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Waelter S, Boeddrich A, Lurz R et al. Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 2001; 12(5): 1393–1407.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Wang H, Strandin T, Hepojoki J et al. Degradation and aggresome formation of the Gn tail of the apathogenic Tula hantavirus. J Gen Virol 2009; 90(Pt 12):2995–3001.PubMedCrossRefGoogle Scholar
  71. 71.
    Stenoien DL, Mielke M, Mancini MA. Intranuclear ataxin1 inclusions containbothfast-and slow-exchanging components. Nat Cell Biol 2002; 4(10):806–810.PubMedCrossRefGoogle Scholar
  72. 72.
    DiFiglia M, Sapp E, Chase KO et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997; 277(5334): 1990–1993.CrossRefGoogle Scholar
  73. 73.
    Eriguchi M, Mizuta H, Luo S et al. Alpha Pix enhances mutant huntingtin aggregation. J Neurol Sci 2010; 290(1–2):80–85.PubMedCrossRefGoogle Scholar
  74. 74.
    Shao J, Welch WJ, Diprospero NA et al. Phosphorylation of profilin by ROCK 1 regulates polyglutamine aggregation. Mol Cell Biol 2008; 28(17):5196–5208.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Burnett BG, Andrews J, Ranganathan S et al. Expression of expanded polyglutamine targets profilin for degradation and alters actin dynamics. Neurobiol Dis 2008; 30(3):365–374.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Angeli S, Shao J, Diamond MI. F-actin binding regions on the androgen receptor and huntingtin increase aggregation and alter aggregate characteristics. PLoS One 2010; 5(2):e9053.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kim YJ, Yi Y, Sapp E et al. Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington’s disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci U S A 2001; 98(22):12784–12789.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Landles C, Sathasivam K, Weiss A et al. Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease. J Biol Chem 2010; 285(12):8808–8823.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Li X, Li H, Li XJ. Intracellular degradation of misfolded proteins in polyglutamine neurodegenerative diseases. Brain Res Rev 2008; 59(1):245–252.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Sieradzan KA, Mechan AO, Jones L et al. Huntington’s disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp Neurol 1999; 156(1):92–99.PubMedCrossRefGoogle Scholar
  81. 81.
    Martindale D, Hackam A, Wieczorek A et al. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet 1998; 18(2): 150–154.PubMedCrossRefGoogle Scholar
  82. 82.
    Hackam AS, Singaraja R, Wellington CL et al. The influence of huntingtin protein size onnuclear localization and cellular toxicity. J Cell Biol 1998; 141(5): 1097–1105.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Warby SC, Doty CN, Graham RK et al. Activated caspase’6 and caspase’6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum Mol Genet 2008; 17(15):2390–2404.PubMedCrossRefGoogle Scholar
  84. 84.
    Graham RK, Deng Y, Slow EJ et al. Cleavage at the caspase’6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 2006; 125(6):1179–1191.PubMedCrossRefGoogle Scholar
  85. 85.
    Schilling B, Gafni J, Torcassi C et al. Huntingtin phosphorylation sites mapped by mass spectrometry. Modulation of cleavage and toxicity. J Biol Chem 2006; 281(33):23686–23697.PubMedGoogle Scholar
  86. 86.
    Aiken CT, Steffan JS, Guerrero CM et al. Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J Biol Chem 2009; 284(43):29427–29436.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Rockabrand E, Slepko N, Pantalone A et al. The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 2007; 16(1):61–77.PubMedCrossRefGoogle Scholar
  88. 88.
    Steffan JS, Agrawal N, Pallos J et al. SUMO modification of Huntingtin and Huntington’s disease pathology. Science 2004; 304(5667):100–104.PubMedCrossRefGoogle Scholar
  89. 89.
    Yanai A, Huang K, Kang R et al. Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci 2006; 9(6):824–831.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Jeong H, Then F, Melia TJ Jr et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009; 137(1):60–72.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Humbert S, Bryson EA, Cordelieres FP et al. The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2002; 2(6):831–837.PubMedCrossRefGoogle Scholar
  92. 92.
    Rangone H, Poizat G, Troncoso J et al. The serum-and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur J Neurosci 2004; 19(2):273–279.PubMedCrossRefGoogle Scholar
  93. 93.
    Zuccato C, Valenza M, Cattaneo E. Molecularmechanisms andpotential therapeutical targets in Huntington’s disease. Physiol Rev 2010; 90(3):905–981.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Li SH, Li XJ. Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 2004; 20(3):146–154.PubMedCrossRefGoogle Scholar
  95. 95.
    Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000; 23:217–247.CrossRefPubMedGoogle Scholar
  96. 96.
    Marsh JL, Walker H, Theisen H et al. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum Mol Genet 2000; 9(1):13–25.PubMedCrossRefGoogle Scholar
  97. 97.
    Zeitlin S, Liu JP, Chapman DL et al. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 1995; 11(2):155–163.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 2000; 26(3):300–306.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Leavitt BR, Guttman JA, Hodgson JG et al. Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. Am J Hum Genet 2001; 68(2):313–324.PubMedCrossRefGoogle Scholar
  100. 100.
    Van Raamsdonk JM, Pearson J, Murphy Z et al. Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease. BMC Neurosci 2006; 7:80.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Leavitt BR, van Raamsdonk JM, Shehadeh J et al. Wild-type huntingtin protects neurons from excitotoxicity. J Neuro chem 2006;96(4):1121–1129.Google Scholar
  102. 102.
    HoL W, Brown R, Maxwell M et al. Wildtype Huntingtin reduces the cellulartoxicity of mutant Huntingtin in mammalian cell models of Huntington’s disease. J Med Genet 2001; 38(7):450–452.CrossRefGoogle Scholar
  103. 103.
    Busch A, Engemann S, Lurz R et al. Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington’s disease. J Biol Chem 2003; 278(42):41452–41461.PubMedCrossRefGoogle Scholar
  104. 104.
    Perez MK, Paulson HL, Pendse SJ et al. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 1998; 143(6):1457–1470.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Kazantsev A, Preisinger E, Dranovsky A et al. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc Natl Acad Sci US A 1999;96(20):11404–11409.CrossRefGoogle Scholar
  106. 106.
    Steffan JS, Kazantsev A, Spasic-Boskovic O et al. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A 2000; 97(12):6763–6768.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Holbert S, Denghien I, Kiechle T et al. The Gin-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc Natl Acad Sci U S A 2001; 98(4):1811–1816.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Chai Y, Wu L, Griffin JD et al. The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease. J Biol Chem 2001; 276(48):44889–44897.PubMedCrossRefGoogle Scholar
  109. 109.
    Kim S, Nollen EA, Kitagawa K et al. Polyglutamine protein aggregates are dynamic. Nat Cell Biol 2002; 4(10):826–831.PubMedCrossRefGoogle Scholar
  110. 110.
    Gidalevitz T, Ben-Zvi A, Ho KH et al. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 2006; 311(5766):1471–1474.PubMedCrossRefGoogle Scholar
  111. 111.
    Prahlad V, Morimoto RI. Integrating the stress response: lessons for neurodegenerative diseases from C. elegans. Trends Cell Biol 2009; 19(2):52–61.PubMedCrossRefGoogle Scholar
  112. 112.
    Cornett J, Cao F, Wang CE et al. Polyglutamine expansion of huntingtin impairs its nuclear export. Nat Genet 2005; 37(2):198–204.PubMedCrossRefGoogle Scholar
  113. 113.
    Lee WC, Yoshihara M, Littleton JT. Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington’s disease. Proc Natl Acad Sci U S A 2004; 101(9):3224–3229.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Milnerwood AJ, Raymond LA. Corticostriatal synaptic function in mouse models of Huntington’s disease: early effects of huntingtin repeat length and protein load. J Physiol 2007; 585(Pt 3):817–831.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Schaffar G, Breuer P, Boteva R et al. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 2004; 15(1):95–105.PubMedCrossRefGoogle Scholar
  116. 116.
    Piccioni F, Pinton P, Simeoni S et al. Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. FASEB J 2002; 16(11): 1418–1420.PubMedCrossRefGoogle Scholar
  117. 117.
    Harjes P, Wanker EE. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 2003; 28(8):425–433.PubMedCrossRefGoogle Scholar
  118. 118.
    Strehlow AN, Li JZ, Myers RM. Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space. Hum Mol Genet 2007; 16(4):391–409.PubMedCrossRefGoogle Scholar
  119. 119.
    Monoi H, Futaki S, Kugimiya S et al. Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases. Biophys J 2000; 78(6):2892–2899.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Suopanki J, Götz C, Lutsch G et al. Interaction of huntingtin fragments with brain membranes — clues to early dysfunction in Huntington’s disease. J Neurochem 2006; 96(3):870–884.PubMedCrossRefGoogle Scholar
  121. 121.
    Ren P-H, Lauckner JE, Kachirskaia I et al. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol 2009; 11(2):219–225.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Kegel KB, Sapp E, Alexander J et al. Polyglutamine expansion in huntingtin alters its interaction with phospholipids. J Neurochem 2009; 110(5):1585–1597.PubMedCrossRefGoogle Scholar
  123. 123.
    Kegel KB, Schewkunow V, Sapp E et al. Polyglutamine expansion in huntingtin increases its insertion into lipid bilayers. Biochem Biophys Res Commun 2009; 387(3):472–475.PubMedCrossRefGoogle Scholar
  124. 124.
    Lashuel HA, Petre BM, Wall J et al. Alpha-synuclein, especially the Parkinson’s disease-associatedmutants, forms pore-like annular and tubular protofibrils. J Mol Biol 2002; 322(5):1089–1102.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Brignull HR, Morley JF, Garcia SM et al. Modeling polyglutamine pathogenesis in C. elegans. Methods Enzymol 2006; 412:256–282.PubMedCrossRefGoogle Scholar
  126. 126.
    Diguet E, Petit F, Escartin C et al. Normal aging modulates the neurotoxicity of mutant huntingtin. PLoS One 2009; 4(2):e4637.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    David DC, Ollikainen N, Trinidad JC et al. Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol 2010; 8(8):el000450.CrossRefGoogle Scholar
  128. 128.
    Tonkiss J, Calderwood SK. Regulation of heat shock gene transcriptioninneuronal cells. Int J Hyperthermia 2005;21(5):433–444.PubMedCrossRefGoogle Scholar
  129. 129.
    Cuervo AM, Dice JF. Regulation of Iamp2a levels in the lysosomal membrane. Traffic 2000; 1(7):570–583.PubMedCrossRefGoogle Scholar
  130. 130.
    Duennwald ML, Lindquist S. Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity. Genes Dev 2008; 22(23):3308–3319.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Jana NR, Zemskov EA, Wang G et al. Altered proteasomal function due to the expression of polyglutamine-expandedtruncated N-terminalhuntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet 2001; 10(10): 1049–1059.PubMedCrossRefGoogle Scholar
  132. 132.
    Sarkar S, Rubinsztein DC. Huntington’s disease: degradation of mutant huntingtin by autophagy. FEBS J 2008; 275(17):4263–4270.PubMedCrossRefGoogle Scholar
  133. 133.
    Li X, Wang CE, Huang S et al. Inhibitingthe ubiquitin-proteasome system leadsto preferential accumulation of toxic N-terminal mutant huntingtin fragments. Hum Mol Genet 2010; 19(12):2445–2455.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Ciechanover A, Brundin P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 2003; 40(2):427–446.PubMedCrossRefGoogle Scholar
  135. 135.
    Abel A, Walcott J, Woods J et al. Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 2001; 10(2):107–116.PubMedCrossRefGoogle Scholar
  136. 136.
    Stenoien DL, Cummings CJ, Adams HP et al. 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 Mol Genet 1999; 8(5):731–741.PubMedCrossRefGoogle Scholar
  137. 137.
    Mitsui K, Nakayama H, Akagi T et al. Purification of polyglutamine aggregates and identification of elongation factor-1alpha and heat shock protein 84 as aggregate-interacting proteins. J Neurosci 2002; 22(21):9267–9277.PubMedCrossRefGoogle Scholar
  138. 138.
    Khan LA, Bauer PO, Miyazaki H et al. Expanded polyglutamines impair synaptic transmission and ubiquitin-proteasome system in Caenorhabditis elegans. J Neurochem 2006; 98(2):576–587.PubMedCrossRefGoogle Scholar
  139. 139.
    Bowman AB, Yoo SY, Dantuma NP et al. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet 2005; 14(5):679–691.PubMedCrossRefGoogle Scholar
  140. 140.
    Bett JS, Cook C, Petrucelli L et al. The ubiquitin-proteasome reporter GFPu does not accumulate in neurons of the R6/2 transgenic mouse model of Huntington’s disease. PLoS One 2009; 4(4):e5128.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Wang J, Wang CE, Orr A et al. Impaired ubiquitin-proteasome system activity in the synapses of Huntington’s disease mice. J Cell Biol 2008; 180(6): 1177–1189.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Warrick JM, Chan HY, Gray-Board GL et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 1999; 23(4):425–428.PubMedCrossRefGoogle Scholar
  143. 143.
    Chai Y, Koppenhafer SL, Bonini NM et al. Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci 1999; 19(23): 10338–10347.PubMedCrossRefGoogle Scholar
  144. 144.
    Lotz GP, Legleiter J, Aron R et al. Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle. J Biol Chem 2010.Google Scholar
  145. 145.
    Behrends C, Langer CA, Boteva R et al. Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol Cell 2006; 23(6):887–897.PubMedCrossRefGoogle Scholar
  146. 146.
    Heng MY, Detloff PJ, Paulson HL et al. Early alterations of autophagy in Huntington disease-like mice. Autophagy 2010; 6(8):1206–1208.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Tung YT, Hsu WM, Lee H et al. The evolutionary conserved interaction between LC3 and p62 selectively mediates autophagy-dependent degradation of mutant huntingtin. Cell Mol Neurobiol 2010; 30(5):795–806.PubMedCrossRefGoogle Scholar
  148. 148.
    Martinez-Vicente M, Talloczy Z, Wong E et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 2010; 13(5):567–576.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Ravikumar B, Vacher C, Berger Z et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly andmouse models of Huntington disease. Nat Genet 2004; 36(6):585–595.PubMedCrossRefGoogle Scholar
  150. 150.
    Hara T, Nakamura K, Matsui M et al. Suppression of basal autophagy inneural cells causes neurodegenerative disease in mice. Nature 2006; 441(7095):885–889.CrossRefGoogle Scholar
  151. 151.
    Komatsu M, Waguri S, Chiba T et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441(7095):880–884.CrossRefGoogle Scholar
  152. 152.
    Metzger S, Saukko M, Van Che H et al. Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum Genet 2010; 128(4):453–459.PubMedCrossRefGoogle Scholar
  153. 153.
    Kegel KB, Kim M, Sapp E et al. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tabulation, and autophagy. J Neurosci 2000; 20(19):7268–7278.PubMedCrossRefGoogle Scholar
  154. 154.
    Sapp E, Schwarz C, Chase K et al. Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol 1997; 42(4):604–612.PubMedCrossRefGoogle Scholar
  155. 155.
    Yamada M, Tsuji S, Takahashi H. Pathology of CAG repeat diseases. Neuropathology 2000; 20(4):319–325.PubMedCrossRefGoogle Scholar
  156. 156.
    Yamada M, Tsuji S, Takahashi H. Involvement of lysosomes in the pathogenesis of CAG repeat diseases. Ann Neurol 2002; 52(4):498–503.PubMedCrossRefGoogle Scholar
  157. 157.
    Thompson LM, Aiken CT, Kaltenbach LS et al. IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol 2009; 187(7):1083–1099.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Cuervo AM, Stefanis L, Fredenburg R et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004; 305(5688): 1292–1295.PubMedCrossRefGoogle Scholar
  159. 159.
    Li LB, Yu Z, Teng X et al. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 2008;453(7198):1107–1111.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Mankodi A, Logigian E, Callahan L et al. Myotonic dystrophy intransgenic mice expressing an expanded CUG repeat. Science 2000; 289(5485):1769–1773.PubMedCrossRefGoogle Scholar
  161. 161.
    Amack JD, Paguio AP, Mahadevan MS. Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model. Hum Mol Genet 1999; 8(11):1975–1984.PubMedCrossRefGoogle Scholar
  162. 162.
    Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicingis associated with insulin resistance in myotonic dystrophy. Nat Genet 2001; 29(1):40–47.CrossRefPubMedGoogle Scholar
  163. 163.
    Mankodi A, Takahashi MP, Jiang H et al. Expanded CUG repeats trigger aberrant splicing of C1C′-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 2002; 10(1):35–44.PubMedCrossRefGoogle Scholar
  164. 164.
    Taneja KL, McCurrach M, Schalling M et al. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 1995; 128(6):995–1002.PubMedCrossRefGoogle Scholar
  165. 165.
    Liquori CL, Ricker K, Moseley ML et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 2001; 293(5531):864–867.PubMedCrossRefGoogle Scholar
  166. 166.
    Koob MD, Moseley ML, Schut LJ et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet 1999; 21(4):379–384.PubMedCrossRefGoogle Scholar
  167. 167.
    Buraczynska MJ, Van Keuren ML, Buraczynska KM et al. Construction of human embryonic cDNA libraries: HD, PKD1 and BRCA1 are transcribed widely during embryogenesis. Cytogenet Cell Genet 1995; 71(2): 197–202.PubMedCrossRefGoogle Scholar
  168. 168.
    Sathasivam K, Hobbs C, Turmaine M et al. Formation of polyglutamine inclusions in non-CNS tissue. Hum Mol Genet 1999; 8(5):813–822.PubMedCrossRefGoogle Scholar
  169. 169.
    Bradford JW, Li S, Li XJ. Polyglutamine toxicity in non-neuronal cells. Cell Res 2010; 20(4):400–407.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Ribchester RR, Thomson D, Wood NI et al. Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington’s disease mutation. Eur J Neurosci 2004; 20(11):3092–3114.PubMedCrossRefGoogle Scholar
  171. 171.
    Andreassen OA, Dedeoglu A, Stanojevic V et al. Huntington’s disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression. Neurobiol Dis 2002; 11(3): 410–424.PubMedCrossRefGoogle Scholar
  172. 172.
    Mihm MJ, Amann DM, Schanbacher BL et al. Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 2007; 25(2):297–308.PubMedCrossRefGoogle Scholar
  173. 173.
    Huribert MS, Zhou W, Wasmeier C et al. Mice transgenic for an expanded CAG repeat in the Huntington’s disease gene develop diabetes. Diabetes 1999; 48(3):649–651.CrossRefGoogle Scholar
  174. 174.
    Moffitt H, McPhail GD, Woodman B et al. Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington’s disease. PLoS One 2009; 4(11):e8025.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Fuentealba LC, Eivers E, Geissert D et al. Asymmetric mitosis: unequal segregation of proteins destined for degradation. Proc Natl Acad Sci U S A 2008; 105(22):7732–7737.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Rujano MA, Bosveld F, Salomons FA et al. Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol 2006; 4(12):e417.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Morley JF, Brignull HR, Weyers JJ et al. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A 2002; 99(16):10417–10422.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Hobbs NZ, Barnes J, Frost C et al. Onset and progression of pathologic atrophy in Huntington disease: a longitudinal MR imaging study. AJNR Am J Neuroradiol 2010; 31(6): 1036–1041.PubMedCrossRefGoogle Scholar
  179. 179.
    Nopoulos PC, Aylward EH, Ross CA et al. Smaller intracranial volume in prodromal Huntington’s disease: evidence for abnormal neurodevelopment. Brain 2010.Google Scholar
  180. 180.
    Molero AE, Gokhan S, Gonzalez S et al. Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington’s disease. Proc Natl Acad Sci U S A 2009; 106(51):21900–21905.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Powers ET, Morimoto RI, Dillin A et al. Biological and chemical approaches to diseases of proteostasis deficiency. Ann Rev Biochem 2009; 78(1):959–991.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Saskia Polling
    • 1
  • Andrew F. Hill
    • 1
  • Danny M. Hatters
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of MelbourneMelbourneAustralia

Personalised recommendations