Therapeutic approaches to polyglutamine diseases: Combating protein misfolding and aggregation

Current Pharmaceutical Design

Volumn 12, Issue 20, 2006, Pages 2543-2555

  Herbst, Martin ^a   Wanker, Erich E ^a  

^a MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE   (Germany)

Author keywords

Cell free aggrtegation assay; Cellular transcription factors; Geldanamycin; Hsp 70; Mutant polyQ proteins; SCA1 transgenic mice

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; 6 (1,3 DIOXO 1H,3H BENZO[DE]ISOQUINOLIN 2 YL) N HYDROXYHEXANAMIDE; ALPHA GALACTOSIDASE; ATAXIN 3; ATAXIN 7; BENZOTHIAZOLE DERIVATIVE; BENZYLOXYCARBONYLVALYLALANYLASPARTYL FLUOROMETHYL KETONE; BETA GALACTOSIDASE; BUTYRIC ACID; CELL PROTEIN; CYCLIC AMP; CYSTAMINE; GELDANAMYCIN; HEAT SHOCK PROTEIN 40; HEAT SHOCK PROTEIN 70; HEAT SHOCK PROTEIN 90; HISTONE DEACETYLASE INHIBITOR; HUNTINGTIN; MINOCYCLINE; POLYGLUTAMINE; PRION PROTEIN; RAPAMYCIN; RAPAMYCIN DERIVATIVE; REMACEMIDE; RILUZOLE; TREHALOSE; TRICHOSTATIN A; UBIDECARENONE; UNINDEXED DRUG; VORINOSTAT;

ALZHEIMER DISEASE; AMINO TERMINAL SEQUENCE; AUTOPHAGY; AUTOSOMAL DOMINANT DISORDER; BLOOD BRAIN BARRIER; BRAIN ATROPHY; CELL PROTECTION; CLINICAL TRIAL; CONFORMATIONAL TRANSITION; CORRELATION FUNCTION; CYTOTOXICITY; DEGENERATIVE DISEASE; DISEASE SEVERITY; DRUG MECHANISM; ENZYME INHIBITION; EXCITOTOXICITY; FLUORESCENCE RESONANCE ENERGY TRANSFER; HEAT SHOCK RESPONSE; HEAT STRESS; HUMAN; HUNTINGTON CHOREA; KENNEDY DISEASE; LONG TERM POTENTIATION; NERVE CELL NECROSIS; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; ONSET AGE; PARKINSON DISEASE; PATHOGENESIS; PATHOPHYSIOLOGY; POLYGLUTAMINE DISEASE; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; RNA INTERFERENCE; SYMPTOM; TRANSCRIPTION REGULATION; UNSPECIFIED SIDE EFFECT;

ANIMALS; CELL DEATH; HEAT-SHOCK PROTEINS; HUMANS; NEURODEGENERATIVE DISEASES; NEURONS; PEPTIDES; PROTEIN FOLDING;

EID: 33745750191     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161206777698828     Document Type: Review

References (176)

1. Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative disease. Science 2002; 296(5575): 1991-5.
2. Michalik A, Van Broeckhoven C. Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 2003; 12(Spec No 2): R173-86.
3. Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med 2004; 10 Suppl: S10-7.
4. Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000; 23: 217-47.
5. Taroni F, DiDonato S. Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci 2004; 5(8): 641-55.
6. Grimbergen YA, Roos RA. Therapeutic options for Huntingtons disease. Curr Opin Investig Drugs 2003; 4(1): 51-4.
7. Bonelli RM, Wenning GK, Kapfhammer HP. Huntington's disease: present treatments and future therapeutic modalities. Int Clin Psychopharmacol 2004; 19(2): 51-62.
8. Bates GP, Benn, C. The polyglutamine diseases. In: Bates GP, Harper PS, Jones L, ed. Huntington's disease: Oxford University Press; 2002; p. 429-472.
9. Ross CA. When more is less: pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 1995; 15: 493-496.
10. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352(6330): 77-9.
11. Group HS. 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): 971-83.
12. Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet Al, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993; 4(3): 221-6.
13. Bates GP, Hockly E. Experimental therapeutics in Huntington's disease: are models useful for therapeutic trials? Curr Opin Neurol 2003; 16(4): 465-70.
14. Sams-Dodd F. Target-based drug discovery: is something wrong? Drug Discov Today 2005; 10(2): 139-47.
15. Lansbury PT, Jr. Back to the future: the 'old-fashioned' way to new medications for neurodegeneration. Nat Med 2004; 10 Suppl: S51-7.
16. Chen S, Berthelier V, Yang W, Wetzel R. Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J Mol Biol 2001; 311(1): 173-82.
17. Masino L, Pastore A. Glutamine repeats: structural hypotheses and neurodegeneration. Biochem Soc Trans 2002; 30(4): 548-51.
18. Perutz MF, Staden R, Moens L, De Baere I. Polar zippers. Curr Biol 1993; 3(5): 249-53.
19. Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 2000; 10(2): 524-30.
20. Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, 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): 1393-407.
21. Sakahira H, Breuer P, Hayer-Hartl MK, Hard FU. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci USA 2002; 99(Suppl 4): 16412-8.
22. Perutz MF, Johnson T, Suzuki M, Finch JT. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 1994:91(12):5355-8.
23. Sharma D, Sharma S, Pasha S, Brahmachari SK. Peptide models for inherited neurodegenerative disorders: conformation and aggregation properties of long polyglutamine peptides with and without interruptions. FEBS Left 1999,456(1): 181-185.
24. Chen S, Berthelier V, Hamilton JB, O'Nuallain B, Wetzel R. Amyloid-like features of polyglutamine aggregates and their assembly kinetics. Biochemistry 2002; 41(23): 7391-9.
25. Poirier MA, Li H, Macosko J, Cai S, Amzel M, Ross CA. Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrilization. J Biol Chem 2002; 277(43): 41032-7.
26. Tanaka M, Morishima I, Akagi T, Hashikawa T, Nukina N. Intra-and intermolecular beta-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for polyglutamine diseases. J Biol Chem 2001; 276(48): 45470-5.
27. Chen S, Wetzel R. Solubilization and disaggregation of polyglutamine peptides. Protein Sci 2001; 10(4): 887-91.
28. Bevivino AE, Loll PJ. An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel beta - fibrils. Proc Natl Acad Sci USA 2001; 98(21): 11955-60.
29. Monoi H. New tubular single-stranded helix of poly-L-amino acids suggested by molecular mechanics calculations: I. Homopolypeptides in isolated environments. Biophys J 1995; 69(3): 1130-41.
30. Monoi H, Futaki S, Kugimiya S, Minakata H, Yoshihara K. Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases. Biophys J 2000; 78(6): 2892-9.
31. Wacker JL, Zareie MH, Fong H, Sarikaya M, Muchowski PJ, Hsp70 and Hsp4O attenuate formation of spherical and annular polyglutamine of oligomers by partitioning monomer. Nat Struct Mol Biol 2004; 11(12): 1215-22.
32. Temussi PA, Masino L, Pastore A. From Alzheimer to Huntington: why is a structural understanding so difficult? EMBO J 2003; 22 (3): 355-61.
33. Dobson CM. Protein folding and misfolding. Nature 2003; 426 (6968): 884-90.
34. Cohen FE, Kelly JW. Therapeutic approaches to protein-misfolding diseases. Nature 2003; 426(6968): 905-9.
35. Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90(3): 549-58.
36. Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc Natl Acad Sci USA 1999; 96(8): 4604-9.
37. Chen S, Ferrone FA, Wetzel R. Huntington's disease age-of-onset linked to polyglutamine aggregation nucleation. Proc Natl Acad Sci USA 2002; 99(18): 11884-9.
38. Roizin L. The relevance of the structural co-factor (chemogenic lesion) in adverse and toxic reactions of neuropsychotropic agents. Prog Neuropsychopharmacol 1979; 3(1-3): 245-57.
39. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp Ali, Ross CA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90(3): 537-48.
40. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997; 277(5234): 1990-3.
41. Paulson HL, Perez MK, Tottier Y, Trojanowski JQ, Subramony SH, Das SS, et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 1997; 19: 333-344.
42. Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH, Pittman RN, et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 1998; 93(6): 939-49.
43. Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN. Recruitment and the role of nuclear localization in polyglutamine- mediated aggregation. J Cell Biol 1998; 143(6): 1457-70.
44. Suhr ST, Senut MC, Whitelegge JP, Faull KE, Cuizon DB, Gage FH. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J Cell Biol 2001; 153(2): 283-294.
45. Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M, et al. Hippi and Hip-1 are molecular accomplices that mediate the recruitment and activation of caspase-8 by an novel mechanism that may contribute to neuronal death in Huntington's disease. Nat Cell Biol 2002; 4(2): 95-105.
46. Bates G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet 2003; 361(9369): 1642-4.
47. Sisodia SS. Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell 1998; 95(1): 1-4.
48. Lee HG, Petersen RB, Zhu X, Honda K, Aliev G, Smith MA, et al. Will preventing protein aggregates live up to its promise as prophylaxis against neurodegenerative diseases? Brain Pathol 2003; 13(4): 630-8.
49. Ordway JM, Tallaksen-Greene S, Gutekunst CA, Bernstein EM, Cearly JA, Wiener HW, et al. Ectopically expressed CAG repeat cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 1997; 91: 753-763.
50. Gomez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, et al. Quantitative neuropathological changes in presymptomatic Huntington's disease. Ann Neurol 2001; 49(1): 29-34.
51. Yang W, Dunlap JR, Andrews RB, Wetzel R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum Mol Genet 2002; 11(23): 2905-17.
52. Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, et al. Intramuclear 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; 4(6): 387-97.
53. Kuemmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, Beal MF, et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann Neurol 1999; 46(6): 842-9.
54. Gutekunst C-A, Li S-H, Yi H, Mulroy JS, Kuemmerle S, Jones R, et al. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J Neuroscience 1999; 19: 2522-2534.
55. Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, et al. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 1999; 23(1): 181-92.
56. Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO, Jr., et al. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet 1998; 20(2): 198-202.
57. 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; 95(1): 55-66.
58. Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine- induced disease in SCA1 transgenic mice. Cell 1998; 95(1): 41-53.
59. Skinner PJ, Vierra-Green CA, Emamian E, Zoghbi HY, Orr HT. Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic mice. Neuromolecular Med 2002; 1(1): 33-42.
60. Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins. J Cell Biol 1998; 143(7): 1883-98.
61. Taylor JP, Tanaka F, Robitschek J, Sandoval CM, Taye A, Markovic-Plese S, et al. Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet 2003; 12(7): 749-57.
62. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004; 431(7010): 805-10.
63. Yoo SY, Pennesi ME, Weeber EJ, Xu B, Atkinson R, Chen S, et al. SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 2003; 37(3): 383-401.
64. Harper JD, Wong SS, Lieber CM, Lansbury PT, Jr. Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease. Biochemistry 1999; 38(28): 8972-80.
65. Klein WL, Krafft GA, Finch CE. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci 2001; 24(4): 219-24.
66. Harper JD, Lieber CM, Lansbury PT, Jr. Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-beta protein. Chem Biol 1997; 4(12): 951-9.
67. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abetal-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 1998; 95(11): 6448-53.
68. Conway KA, Lee SJ, Rochet JC, Ding TT, Harper JD, Williamson RE, et al. Accelerated oligomerization by Parkinson's disease linked alpha-synuclein mutants. Ann N Y Acad Sci 2000; 920: 42-5.
69. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416(6880): 535-9.
70. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002; 416(6882): 507-11.
71. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003; 300(5618): 486-9.
72. Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, et al. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 2004; 15(1): 95-105.
73. Steffan JS, Thompson LM. Targeting aggregation in the development of therapeutics for the treatment of Huntington's disease and other polyglutamine repeat diseases. Expert Opin Ther Targets 2003; 7(2): 201-13.
74. Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 2004; 10(8): 816-20
75. Lunkes A, Lindenberg KS, Ben-Haiem L, Weber C, Devys D, Landwehrmeyer GB, et al. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol Cell 2002; 10(2): 259-69.
76. Wellington CL, Hayden MR. Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches. Clin Genet 2000; 57(1): 1-10.
77. Citron M. Strategies for disease modification in Alzheimer's disease. Nat Rev Neurosci 2004; 5(9): 677-85.
78. Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N, et al. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc Natl Acad Sci USA 2000; 97(12): 6739-44.
79. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 2003; 4(1): 49-60.
80. Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 2000; 101 (1): 57-661
81. Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS, Welch WJ, Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones 1996; 1(2): 117-25.
82. Miroy GJ, Lai Z, Lashuel HA, Peterson SA, Strang C, Kelly JW. Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc Natl Acad Sci USA 1996; 93: 15051-15056.
83. Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci USA 2000; 97(4): 1796-801.
84. Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW. Chemical chaperones increase the cellular activity of N370S beta -glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci USA 2002; 99(24): 15428-33.
85. Howard M, Welch WJ. Manipulating the folding pathway of delta F508 CFTR using chemical chaperones. Methods Mol Med 2002; 70: 267-75.
86. Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR. Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 1996; 271(2): 635-8.
87. Fischer H, Fukuda N, Barbry P, Illek B, Sartori C, Matthay MA. Partial restoration of defective chloride conductance in DeltaF508 CF mice by trimethylamine oxide. Am J Physiol Lung Cell Mol Physiol 2001; 281(1): L52-7.
88. Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I. Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol Dis 2002; 10(2): 88-99.
89. Nagao Y, Ishiguro H, Nukina N. DMSO and glycerol reduce bacterial death induced by expression of truncated N-terminal huntingtin with expanded polyglutamine tracts. Biochim Biophys Acta 2000; 1502(2): 247-56.
90. Matsuda J, Suzuki O, Oshima A, Yamamoto Y, Noguchi A, Takimoto K, et al. Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis. Proc Natl Acad Sci USA 2003; 100(26): 15912-7.
91. Fan JQ, Ishii S, Asano N, Suzuki Y. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 1999; 5(1): 112-5.
92. Bernier V, Lagace M, Bichet DG, Bouvier M. Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 2004; 15(5): 222-8.
93. Cashman NR, Caughey B. Prion diseases - close to effective therapy? Nat Rev Drug Discov 2004; 3(10): 874-84.
94. Soto C. Plaque busters: strategies to inhibit amyloid formation in Alzheimer's disease. Mol Med Today 1999; 5(8): 343-50.
95. Caughey B, Race RE. Potent inhibition of scrapie-associated PrP accumulation by congo red. J Neurochem 1992; 59(2): 768-71.
96. Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci USA 1994; 91(25): 12243-7.
97. Wanker EE, Scherzinger E, Heiser V, Sittler A, Eickhoff H, Lehrach H. Membrane filter assay for detection of amyloid-like polyglutamine-containing protein aggregates. Methods Enzymol 1999; 309: 375-86.
98. Smith DL, Portier R, Woodman B, Hockly E, Mahal A, Klunk WE, et al. Inhibition of polyglutamine aggregation in R6/2 HD brain slices-complex dose-response profiles. Neurobiol Dis 2001; 8(6): 1017-26.
99. Apostol BL, Kazantsev A, Raffioni S, Illes K, Pallos J, Bodai L, et al. A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila. Proc Nact Acad Sci USA 2003; 100(10): 5950-5.
100. Sanchez I, Mahlke C, Yuan J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 2003; 421(6921): 373-9.
101. Klunk WE, Debnath ML, Pettegrew JW. Development of small molecule probes for the beta-amyloid protein of Alzheimer's disease. Neurobiol Aging 1994; 15(6): 691-8.
102. Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S, et al. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc Natl Acad Sci USA 2002; 99(Suppl 4): 16400-6.
103. Heemskerk J, Tobin AJ, Bain LJ. Teaching old drugs new tricks. Meeting of the Neurodegeneration Drug Screening Consortium, 7-8 April 2002, Washington, DC, USA. Trends Neurosci 2002; 25(10): 494-6.
104. Wang J, Gines S, MacDonald ME, Gusella JF. Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci 2005; 6(1): 1.
105. Tanaka M, Machida Y, Niu S, Ikeda T, Jana NF, Doi H, et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 2004; 10(2): 148-54.
106. Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE, Roark M, et al. A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci USA 2005; 102(3): 892-7.
107. Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001; 413(6857): 739-43.
108. Pollitt SK, Pallos J, Shao J, Desai UA, Ma AA, Thompson LM, et al. A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron 2003; 40(4): 685-94.
109. Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science 2004; 306(5698): 990-5.
110. Kegel KB, Kim M, Sapp E, McIntyre C, Castano JG, Aronin N, et al. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci 2000; 20(19): 7268-78.
111. Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 2002; 11(9): 1107-17
112. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004; 36(6): 585-95.
113. Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, et al. A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Mol Cell 2004; 15(6): 853-65.
114. Green H. Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 1993; 74: 955-956.
115. Kahlem P, Green H, Djian P. Transglutaminase action imitates Huntington's disease: selective polymerization of Huntingtin containing expanded polyglutamine. Mol Cell 1998; 1(4): 595-601.
116. Zainelli GM, Dudek NL, Ross CA, Kim SY, Muma NA. Mutant huntingtin protein: a substrate for transglutaminase 1, 2, and 3. J Neuropathol Exp Neurol 2005; 64(1): 58-65.
117. Igarashi S, Koide R, Shimohata T, Yamada M, Hayashi Y, Takano H, et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet 1998; 18(2): 111-7.
118. Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 2002; 8(2): 143-9.
119. Lorand L. DRPLA aggregation and transglutaminase, revisited [letter]. Nat Genet 1998; 20(3): 231.
120. Lesort M, Lee M, Tucholski J, Johnson GV. Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem 2003; 278(6): 3825-30.
121. Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002; 295(5561): 1852-8.
122. Muchowski PJ, Wacker JL. Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 2005; 6(1): 11-22.
123. Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 1998; 19(2): 148-54.
124. Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 2001; 10(14): 1511-8.
125. Kobayashi Y, Kume A, Li M, Doyu M, Hata M, Ohtsuka K, et al. Chaperones Hsp70 and Hsp4O suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J Biol Chem 2000; 275(12): 8772-8778.
126. Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 1999; 23(4): 425-8.
127. Kazemi-Estarjani P, Benzer S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 2000; 287(5459): 1837-40.
128. Mitsui K, Nakayama H, Akagi T, Nekooki M, Ohtawa K, Takio K, et al. Purification of polyglutamine aggregates and identification of elongation factor-1 alpha and heat shock protein 84 as aggregate-interacting proteins. J Neurosci 2002; 22(21): 9267-77.
129. Ishihara K, Yamagishi N, Saito Y, Adachi H, Kobayashi Y, Sobue G, et al. Hspl05alpha suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity. J Biol Chem 2003; 278(27): 25143-50.
130. Muchowski PJ, Schaffar G, Sittler A, Wanker EE, Hayer-Hartl MK, Hartl FU. Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Nail Acad Sci USA 2000; 97(14): 7841-6.
131. Helmlinger D, Bonnet J, Mandel JL, Trottier Y, Devys D. Hsp70 and Hsp40 chaperones do not modulate retinal phenotype in SCA7 mice. J Biol Chem 2004; 279(53): 55969-77.
132. Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 1998; 94(4): 471-80.
133. Sittler A, Lurz R, Lueder G, Priller J, Lehrach H, Hayer-Hartl MK, et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum Mol Genet 2001; 10(12): 1307-15.
134. Hay DG, Sathasivam K, Tobaben S, Stahl B, Marber M, Mestril R, et al. Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 2004, 13(13): 1389-405.
135. Westerheide SD, Bosman JD, Mbadugha BN, Kawahara TL, Matsumoto G, Kim S, et al. Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 2004, 279(53): 56053-60.
136. Evert BO, Wullner U, Klockgether T. Cell death in polyglutamine diseases. Cell Tissue Res 2000, 301(1): 189-204.
137. Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000; 1(2): 120-9.
138. Vila M. Interfering with programmed cell death in neurodegenerative diseases: insights from experimental animal models. Drug Discov Today 2004; 9(12): 513-4.
139. Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, et al. Inhibition of caspase- 1 slows disease progression in a mouse model of Huntington's disease. Nature 1999; 399(6733): 263-7.
140. Piccioni F, Roman BR, Fischbeck KH, Taylor JP. A screen for drugs that protect against the cytotoxicity of polyglutamine expanded androgen receptor. Hum Mol Genet 2004; 13(4): 437-46.
141. Aiken CT, Tobin AJ, Schweitzer ES. A cell-based screen for drugs to treat Huntington's disease. Neurobiol Dis 2004; 16(3): 546-55.
142. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000; 6(7): 797-801.
143. Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease. Proc Natl Acad Sci USA 2003; 100(18): 10483-7.
144. Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PA, et al. Minocycline and doxycycline are not beneficial in a model of Huntington's disease. Ann Neurol 2003; 51(2): 186-96.
145. Hersch S, Fink K, Vonsattel JP, Friedlander RM. Minocycline is protective in a mouse model of Huntington's disease. Ann Neurol 2003; 54(6): 841.
146. Diguet E, Gross CE, Tison F, Bezard E. Rise and fall of minocycline in neuroprotection: need to promote publication of negative results. Exp Neurol 2004; 189(1): 1-4.
147. Bonelli RM, Hodl AK, Hofmann P, Kapfhammer HP. Neuroprotection in Huntington's disease: a 2-year study on minocycline. Int Clin Psychopharmacol 2004; 19(6): 337-42.
148. Group HS. Minocycline, safety and tolerability in Huntington disease. Neurology 2004; 63(3): 547-9.
149. Thomas M, Ashizawa T, Jankovic J. Minocycline in Huntington's disease: a pilot study. Mov Disord 2004; 19(6): 692-5.
150. Coyle JT, Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 1976; 263(5574): 244-6.
151. McGeer EG, McGeer PL. Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids. Nature 1976; 263(5577): 517-9.
152. Seppi K, Mueller J, Bodner T, Brandauer E, Benke T, Weirich-Schwaiger H, et al. Riluzole in Huntington's disease (HD): an open label study with one year follow up. J Neurol 2001; 248(10): 866-9.
153. Group HS. Dosage effects of riluzole in Huntington's disease: a multicenter placebo-controlled study. Neurology 2003; 61(11): 1551-6.
154. Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model. Neurosci Lett 2001; 315(3): 149-53.
155. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci 2002; 22(5): 1592-9.
156. Group HS. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 2001; 57(3): 397-404.
157. Cha JH. Transcriptional dysregulation in Huntington's disease. Trends Neurosci 2000; 23(9): 387-92.
158. Sugars KL, Rubinsztein DC. Transcriptional abnormalities in Huntington disease. Trends Genet 2003; 19(5): 233-8.
159. McCampbell A, Fischbeck KH. Polyglutamine and CBP: fatal attraction? Nat Med 2001; 7(5): 528-30.
160. Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, et al. Spl and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 2002; 296(5576): 2238-43:
161. McCampbell A., Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, et al. CREB-binding protein sequestration by expanded polyglutamine. Human Molecular Genetics 2000; 9(14): 2197-2202.
162. Nucifora FC, Sasaki M, Peters W, Huang H, Cooper JK, Yamada M, et al. Interference by Huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science 2001; 291(5512): 2423-2428.
163. McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KH. Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci USA 2001; 98(26): 15179-84.
164. Mantamadiotis T, Lemberger T, Bleckmann SC, Kern H, Kretz O, Martin Villalba A, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 2002; 31(1): 47-54.
165. Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci USA 2003; 100(4): 2041-6.
166. Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, et al. Historic deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci 2003; 23(28): 9418-27
167. Corcoran LJ, Mitchison TJ, Liu Q. A novel action of histone deacetylase inhibitors in a protein aggresome disease model. Curr Biol 2004; 14(6): 488-92.
168. Suuronen T, Huuskonen J, Pihlaja R, Kyrylenko S, Salminen A. Regulation of microglial inflammatory response by histone deacetylase inhibitors. J Neurochem 2003; 87(2): 407-16.
169. Holmberg M, Duyckaerts C, Durr A, Cancel G, Gourfinkel-An I, Darnier P, et al. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 1998; 7(5): 913-8.
170. Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 2002; 35(5): 843-54.
171. Katsuno M, Adachi H, Doyu M, Minamiyama M, Sang C, Kobayashi Y, et al. Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 2003; 9(6): 768-73.
172. Bleicher KH, Bohm HJ, Muller K, Alanine AI. Hit and lead generation: beyond high-throughput screening. Nat Rev Drug Discov 2003; 2(5): 369-78.
173. Robitaille Y, Lopes-Cendes I, Becher M, Rouleau G, Clark AW. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 1997; 7(3): 901-26.
174. Murata M. Novel therapeutic effects of the anti-convulsant, zonisamide, on Parkinsons disease. Curr Pharm Des 2004; 10(6): 687-93.
175. Nagatsu T, Sawada M. Inflammatory process in Parkinson's disease: role
176. Tanaka K, Ogawa N. Possibility of non-immunosuppressive immunophilin ligands as potential therapeutic agents for Parkinson's disease. Curr Pharm Des 2004; 10(6): 669-77.