The interplay between the chaperonin TRiC and N-terminal region of Huntingtin mediates Huntington’s Disease aggregation and pathogenesis

Chapter
Part of the Research and Perspectives in Alzheimer's Disease book series (ALZHEIMER)

Abstract

Huntington’s Disease (HD) is a neurodegenerative disorder resulting from an expanded polyglutamine (polyQ) repeat in exon1 of the Huntingtin (Htt) protein. This polyQ expansion causes aggregation of the Htt protein in neuronal cells, which is linked to HD pathogenesis. Recent evidence has shown that Htt aggregation and toxicity are not solely dictated by the polyQ-expanded region but also by sequences flanking the polyQ region, particularly the first N-terminal 17 amino acids of Htt (N17). N17 has been shown to be critical in the Htt aggregation mechanism as well as host many post-translational modifications and interactions with molecular chaperones. Understanding how N17 functions in Htt aggregation and as a general handle for protein quality control will guide design of HD therapeutics.

Keywords

Protein Quality Control Aggregation Propensity polyQ Protein Hydrophobic Face polyQ Tract 
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.

References

  1. Abedini A, Raleigh DP (2009) A critical assessment of the role of helical intermediates in amyloid formation by natively unfolded proteins and polypeptides. Protein Eng Des Sel 22:453–459PubMedCrossRefGoogle Scholar
  2. Aiken CT, Steffan JS, Guerrero CM, Khashwji H, Lukacsovich T, Simmons D, Purcell JM, Menhaji K, Zhu YZ, Green K, Laferla F, Huang L, Thompson LM, Marsh JL (2009) Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. Jo Biol Chem 284:29427–29436CrossRefGoogle Scholar
  3. Atwal RS, Xia J, Pinchev D, Taylor J, Epand RM, Truant R (2007) Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum Mol Genet 16:2600–2615PubMedCrossRefGoogle Scholar
  4. Atwal RS, Xia J, Pinchev D, Taylor J, Epand RM, Truant R (2011) Kinase inhibitors modulate huntingtin cell localization and toxicity. Nature Chem Biol 7:453–452CrossRefGoogle Scholar
  5. Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting Proteostasis for Disease Intervention. Science 319:916–919PubMedCrossRefGoogle Scholar
  6. 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 4:387–397PubMedCrossRefGoogle Scholar
  7. Behrends C, Langer CA, Boteva R, Böttcher UM, Stemp MJ, Schaffar G, Rao BV, Giese A, Kretzschmar H, Siegers K, Hartl FU (2006) Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol Cell 23:887–897PubMedCrossRefGoogle Scholar
  8. Bhattacharyya A, Thakur AK, Chellgren VM, Thiagarajan G, Williams AD, Chellgren BW, Creamer TP, Wetzel R (2006) Oligoproline effects on polyglutamine conformation and aggregation. J Mol Biol 355:524–535PubMedCrossRefGoogle Scholar
  9. Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR (1997) The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 60:1202–1210PubMedGoogle Scholar
  10. Bugg CW, Isas JM, Fischer T, Patterson PH, Langen R (2012) Structural Features and Domain Organization of Huntingtin Fibrils. Biol Chem 287:1739–31746Google Scholar
  11. Chiti F, Dobson C (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333PubMedCrossRefGoogle Scholar
  12. Cooper JK, Schilling G, Peters MF, Herring WJ, Sharp AH, Kaminsky Z, Masone J, Khan FA, Delanoy M, Borchelt DR, Dawson VL, Dawson TM, Ross CA (1998) Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet 7:783–790PubMedCrossRefGoogle Scholar
  13. Darnell G, Orgel JPRO, Pahl R, Meredith SC (2007) Flanking Polyproline Sequences Inhibit β-Sheet Structure in Polyglutamine Segments by Inducing PPII-like Helix Structure. J Mol Biol 374:688–704PubMedCrossRefGoogle Scholar
  14. Darnell GD, Derryberry J, Kurutz JW, Meredith SC (2009) Mechanism of Cis-Inhibition of PolyQ Fibrillation by PolyP: PPII Oligomers and the Hydrophobic Effect. Biophys J 97:2295–2305PubMedCrossRefGoogle Scholar
  15. 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 90:537–548PubMedCrossRefGoogle Scholar
  16. Difiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA, Boyce FM, Aronin N (1995) Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14:1075–1081PubMedCrossRefGoogle Scholar
  17. 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 277:1990–1993PubMedCrossRefGoogle Scholar
  18. Duennwald ML, Jagadish S, Muchowski PJ, Lindquist S (2006) Flanking sequences profoundly alter polyglutamine toxicity in yeast. Proc Natl Acad Sci USA 103:11045–11050PubMedCrossRefGoogle Scholar
  19. Duyao M, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, Ge P, Vonsattel JP, Gusella JF, Joyner AL, Joyner AL, MacDonald ME (1995) Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269:407–410PubMedCrossRefGoogle Scholar
  20. Fiumara F, Fioriti L, Kandel ER, Hendrickson WA (2010) Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins. Cell 143:1121–1135PubMedCrossRefGoogle Scholar
  21. Greiner ER, Yang XW (2011) Huntington's disease: Flipping a switch on huntingtin. Nat Chem Biol 7:412–414PubMedCrossRefGoogle Scholar
  22. Gu X, Greiner ER, Mishra R, Kodali R, Osmand A, Finkbeiner S, Steffan JS, Thompson LM, Wetzel R, Yang XW (2009) Serines 13 and 16 Are Critical Determinants of Full-Length Human Mutant Huntingtin Induced Disease Pathogenesis in HD Mice. Neuron 64:828–840PubMedCrossRefGoogle Scholar
  23. Hackam AS, Singaraja R, Zhang T, Gan L, Hayden MR (1999) In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease. Hum Mol Genet 8:25–33PubMedCrossRefGoogle Scholar
  24. Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332PubMedCrossRefGoogle Scholar
  25. Havel LS, Wang CE, Wade B, Huang B, Li S, Li XJ (2011) Preferential accumulation of N-terminal mutant huntingtin in the nuclei of striatal neurons is regulated by phosphorylation. Hum Mol Genet 20:1424–1437PubMedCrossRefGoogle Scholar
  26. Jayaraman M, Kodali R, Sahoo B, Thakur AK, Mayasundari A, Mishra R, Peterson CB, Wetzel R (2012) Slow Amyloid Nucleation via α-Helix-Rich Oligomeric Intermediates in Short Polyglutamine-Containing Huntingtin Fragments. J Mol Biol 415:881–899PubMedCrossRefGoogle Scholar
  27. Kelley NW, Huang X, Tam S, Spiess C, Frydman J, Pande VS (2009) The Predicted Structure of the Headpiece of the Huntingtin Protein and Its Implications on Huntingtin Aggregation. J Mol Biol 388:919–927PubMedCrossRefGoogle Scholar
  28. Kim MW, Chelliah Y, Kim SW, Otwinowski Z, Bezprozvanny I (2009) Secondary Structure of Huntingtin Amino-Terminal Region. Structure 17:1205–1212PubMedCrossRefGoogle Scholar
  29. Kitamura A, Kubota H, Pack CG, Matsumoto G, Hirayama S, Takahashi Y, Kimura H, Kinjo M, Morimoto RI, Nagata K (2006) Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state. Nat Cell Biol 8:1163–1169PubMedCrossRefGoogle Scholar
  30. Laccone F, Engel U, Holinski-Feder E, Weigell-Weber M, Marczinek K, Nolte D, Morris-Rosendahl DJ, Zühlke C, Fuchs K, Weirich-Schwaiger H, Schlüter G, von Beust G, Vieira-Saecker AM, Weber BH, Riess O (1999) DNA analysis of Huntington's disease: five years of experience in Germany, Austria, and Switzerland. Neurology 53:801–806PubMedCrossRefGoogle Scholar
  31. Leroux MR, Hartl FU (2000) Protein folding: versatility of the cytosolic chaperonin TRiC/CCT. Curr Biol 10:R260–4PubMedCrossRefGoogle Scholar
  32. Lotz GP, Legleiter J, Aron R, Mitchell EJ, Huang SY, Ng C, Glabe C, Thompson LM, Muchowski PJ (2010) Hsp70 and Hsp40 Functionally Interact with Soluble Mutant Huntingtin Oligomers in a Classic ATP-dependent Reaction Cycle. Biol Chem 285:38183–38193CrossRefGoogle Scholar
  33. MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Srinidhi L, Barnes G, Taylor SA, James M, Groot N, MacFarlane H, Jenkins B, Anderson MA, Wexler NS, Gusella JF, Bates GP, Baxendale S, Hummerich H, Kirby S, North M, Youngman S, Mott R, Zehetner G, Sedlacek Z, Poustka A, Frischauf AM, Lehrach H, Buckler AJ, Church D, Doucette-Stamm L, O’Donovan MC, Riba-Ramirez L, Shah M, Stanton VP, Strobel SA, Draths KM, Wales JL, Dervan P, Housman DE, Altherr M, Shiang R, Thompson L, Fielder T, Wasmuth JJ, Tagle D, Valdes J, Elmer L, Allard M, Castilla L, Swaroop M, Blanchard K, Collins FS, Snell R, Holloway T, Gillespie K, Datson N, Shaw D, Harper PS (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRefGoogle Scholar
  34. MacDonald ME, Gusella JF (1996) Huntington’s disease: translating a CAG repeat into a pathogenic mechanism. Curr Opin Neurobiol 6:638–643PubMedCrossRefGoogle Scholar
  35. 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 87:493–506PubMedCrossRefGoogle Scholar
  36. Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22PubMedCrossRefGoogle Scholar
  37. Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR, Lipton SA (2009) Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nature Med 12:1407–1413Google Scholar
  38. Orr HT, Zoghbi HY (2007) Trinucleotide Repeat Disorders. Annu Rev Neurosci 30:575–621PubMedCrossRefGoogle Scholar
  39. Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, Sullivan PG, Steffan JS, Sensi SL, Thompson LM (2006) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 16:61–77PubMedCrossRefGoogle Scholar
  40. Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66PubMedCrossRefGoogle Scholar
  41. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8:397–407PubMedCrossRefGoogle Scholar
  42. 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 14:1065–1074PubMedCrossRefGoogle Scholar
  43. Shirasaki DI, Greiner ER, Al-Ramahi I, Gray M, Boontheung P, Geschwind DH, Botas J, Coppola G, Horvath S, Loo JA, Yang XW (2012) Network Organization of the Huntingtin Proteomic Interactome in Mammalian Brain. Neuron 75:41–57PubMedCrossRefGoogle Scholar
  44. Sivanandam VN, Jayaraman M, Hoop CL, Kodali R, Wetzel R, van der Wel PC (2011) The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils. J Am Chem Soc 133:4558–4566PubMedCrossRefGoogle Scholar
  45. Spiess C, Meyer AS, Reissmann S, Frydman J (2004) Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets. Trends Cell Biol 14:598–604PubMedCrossRefGoogle Scholar
  46. Spiess C, Miller EJ, McClellan AJ, Frydman J (2006) Identification of the TRiC/CCT substrate binding sites uncovers the function of subunit diversity in eukaryotic chaperonins. Mol Cell 24:25–37PubMedCrossRefGoogle Scholar
  47. Steffan JS (2004) SUMO Modification of Huntingtin and Huntington's Disease Pathology. Science 304:100–104PubMedCrossRefGoogle Scholar
  48. Tam S, Geller R, Spiess C, Frydman J (2006) The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nat Cell Biol 8:1155–1162PubMedCrossRefGoogle Scholar
  49. Tam S, Spiess C, Auyeung W, Joachimiak L, Chen B, Poirier MA, Frydman J (2009) The chaperonin TRiC blocks a huntingtin sequence element that promotes the conformational switch to aggregation. Nature Struc Mol Biol 16:1279–1285CrossRefGoogle Scholar
  50. Thakur AK, Jayaraman M, Mishra R, Thakur M, Chellgren VM, Byeon IJ, Anjum DH, Kodali R, Creamer TP, Conway JF, Gronenborn AM, Wetzel R (2009) Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism. Nat Struct Mol Biol 16:380–389PubMedCrossRefGoogle Scholar
  51. Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A, Martinez-Vincente M, Arrasate M, O'Rourke JG, Khashwji H, Lukacsovich T, Zhu YZ, Lau AL, Massey A, Hayden MR, Zeitlin SO, Finkbeiner S, Green KN, LaFerla FM, Bates G, Huang L, Patterson PH, Lo DC, Cuervo AM, Marsh JL, Steffan JS (2009) IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol 187:1083–1099PubMedCrossRefGoogle Scholar
  52. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G, Roberts SA, Gayán J, Brocklebank D, Cherny SS, Cardon LR, Gray J, Dlouhy SR, Wiktorski S, Hodes ME, Conneally PM, Penney JB, Gusella J, Cha JH, Irizarry M, Rosas D, Hersch S, Hollingsworth Z, MacDonald M, Young AB, Andresen JM, Housman DE, De Young MM, Bonilla E, Stillings T, Negrette A, Snodgrass SR, Martinez-Jaurrieta MD, Ramos-Arroyo MA, Bickham J, Ramos JS, Marshall F, Shoulson I, Rey GJ, Feigin A, Arnheim N, Acevedo-Cruz A, Acosta L, Alvir J, Fischbeck K, Thompson LM, Young A, Dure L, O'Brien CJ, Paulsen J, Brickman A, Krch D, Peery S, Hogarth P, Higgins DS Jr, Landwehrmeyer B (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci USA 101:3498–3503PubMedCrossRefGoogle Scholar
  53. Williamson TE, Vitalis A, Crick SL, Pappu RV (2010) Modulation of Polyglutamine Conformations and Dimer Formation by the N-Terminus of Huntingtin. J Mol Biol 396:1295–1309PubMedCrossRefGoogle Scholar
  54. Yam AY, Xia Y, Lin HT, Burlingame A, Gerstein M, Frydman J (2008) Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies. Nat Struct Mol Biol 15:1255–1262PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Biology and BioX ProgramStanford UniversityStanfordUSA

Personalised recommendations