Proteostasis in striatal cells and selective neurodegeneration in Huntington's disease

Frontiers in Cellular Neuroscience

Volumn 8, Issue AUG, 2014, Pages

  Margulis, Julia ^a,b,c   Finkbeiner, Steven ^a,b,c,d  

^a GLADSTONE INSTITUTE OF NEUROLOGICAL DISEASE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d Taube Koret Center for Huntington's Disease Research   (United States)

Author keywords

Autophagy; Huntington's disease; Proteasome; Proteostasis; Striatum

Indexed keywords

EID: 84905690189     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2014.00218     Document Type: Review

References (116)

1. Arrasate, M., and Finkbeiner, S. (2012). Protein aggregates in Huntington's disease. Exp. Neurol. 238, 1-11. doi: 10.1016/j.expneurol.2011.12.013
2. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., and Finkbeiner, S. (2004). Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805-810. doi: 10.1038/nature02998
3. Baldo, B., Soylu, R., and Petersén, Å. (2013). Maintenance of basal levels of autophagy in Huntington's disease mouse models displaying metabolic dysfunction. PLoS ONE 8:e83050. doi: 10.1371/journal.pone.0083050
4. Becher, M. W., Kotzuk, J. A., Sharp, A. H., Davies, S. W., Bates, G. P., Price, D. L., et al. (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. doi: 10.1006/nbdi.1998.0168
5. Bence, N. F., Sampat, R. M., and Kopito, R. R. (2001). Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552-1555. doi: 10.1126/science.292.5521.1552
6. Bennett, E. J., Bence, N. F., Jayakumar, R., and Kopito, R. R. (2005). Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol. Cell 17, 351-365. doi: 10.1016/j.molcel.2004.12.021
7. Berger, Z., Ravikumar, B., Menzies, F. M., Oroz, L. G., Underwood, B. R., Pangalos, M. N., et al. (2006). Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433-442. doi: 10.1093/hmg/ddi458
8. Bett, J. S., Goellner, G. M., Woodman, B., Pratt, G., Rechsteiner, M., and Bates, G. P. (2006). Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REGgamma as a therapeutic target. Hum. Mol. Genet. 15, 33-44. doi: 10.1093/hmg/ddi423
9. Bezprozvanny, I., and Hayden, M. R. (2004). Deranged neuronal calcium signaling and Huntington disease. Biochem. Biophys. Res. Commun. 322, 1310-1317. doi: 10.1016/j.bbrc.2004.08.035
10. Bingol, B., and Schuman, E. M. (2006). Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nat. Cell Biol. 441, 1144-1148. doi: 10.1038/nature04769
11. Bingol, B., Wang, C.-F., Arnott, D., Cheng, D., Peng, J., and Sheng, M. (2010). Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140, 567-578. doi: 10.1016/j.cell.2010.01.024
12. Bonelli, R. M., and Hofmann, P. (2007). A systematic review of the treatment studies in Huntington's disease since 1990. Expert Opin. Pharmacother. 8, 141-153. doi: 10.1517/14656566.8.2.141
13. Carmichael, J., Chatellier, J., Woolfson, A., Milstein, C., Fersht, A. R., and Rubinsztein, D. C. (2000). Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease. Proc. Natl. Acad. Sci. U.S.A. 97, 9701-9705. doi: 10.1073/pnas.170280697
14. Cepeda, C., Colwell, C. S., Itri, J. N., Gruen, E., and Levine, M. S. (1998). Dopaminergic modulation of early signs of excitotoxicity in visualized rat neostriatal neurons. Eur. J. Neurosci. 10, 3491-3497. doi: 10.1046/j.1460-9568.1998.00357.x
15. Chakrabarti, L., Eng, J., Ivanov, N., Garden, G. A., and La Spada, A. R. (2009). Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death. Mol. Brain 2, 24. doi: 10.1186/1756-6606-2-24
16. Charvin, D., Vanhoutte, P., Pages, C., Borrelli, E., Borelli, E., and Caboche, J. (2005). Unraveling a role for dopamine in Huntington's disease: the dual role of reactive oxygen species and D2 receptor stimulation. Proc. Natl. Acad. Sci. U.S.A. 102, 12218-12223. doi: 10.1073/pnas.0502698102
17. Cilenti, L., Ambivero, C. T., Ward, N., Alnemri, E. S., Germain, D., and Zervos, A. S. (2014). Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy. Biochim. Biophys. Acta 1843, 1295-1307. doi: 10.1016/j.bbamcr.2014.03.027
18. Clausen, T., Southan, C., and Ehrmann, M. (2002). The HtrA family of proteases: implications for protein composition and cell fate. Mol. Cell 10, 443-455. doi: 10.1016/S1097-2765(02)00658-5
19. Crouch, P. J., Savva, M. S., Hung, L. W., Donnelly, P. S., Mot, A. I., Parker, S. J., et al. (2011). The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J. Neurochem. 119, 220-230. doi: 10.1111/j.1471-4159.2011.07402.x
20. Damiano, M., Gautier, C. A., Bulteau, A.-L., Ferrando-Miguel, R., Gouarne, C., Paoli, M. G., et al. (2014). Tissue-and cell-specific mitochondrial defect in parkin-deficient mice. PLoS ONE 9:e99898. doi: 10.1371/journal.pone.0099898
21. Davies, S. W., Turmaine, M., Cozens, B. A., DiFiglia, M., Sharp, A. H., Ross, C. A., et al. (1997). Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537-548. doi: 10.1016/S0092-8674(00)80513-9
22. Decuypere, J.-P., Bultynck, G., and Parys, J. B. (2011). A dual role for Ca(2+) in autophagy regulation. Cell Calcium50, 242-250. doi: 10.1016/j.ceca.2011.04.001
23. Diedrich, M., Kitada, T., Nebrich, G., Koppelstaetter, A., Shen, J., Zabel, C., et al. (2011). Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson's disease. Proteome Sci. 9, 59. doi: 10.1186/1477-5956-9-59
24. DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P., et al. (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990-1993. doi: 10.1126/science.277.5334.1990
25. Djakovic, S. N., Schwarz, L. A., Barylko, B., DeMartino, G. N., and Patrick, G. N. (2009). Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 284, 26655-26665. doi: 10.1074/jbc.M109.021956
26. Eden, E., Geva-Zatorsky, N., Issaeva, I., Cohen, A., Dekel, E., Danon, T., et al. (2011). Proteome half-life dynamics in living human cells. Science 331, 764-768. doi: 10.1126/science.1199784
27. Ehlers, M. D. (2003). Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat. Neurosci. 6, 231-242. doi: 10.1038/nn1013
28. Ferrante, R. J., Gutekunst, C. A., Persichetti, F., McNeil, S. M., Kowall, N. W., Gusella, J. F., et al. (1997). Heterogeneous topographic and cellular distribution of huntingtin expression in the normal human neostriatum. J. Neurosci. 17, 3052-3063.
29. Fujikake, N., Nagai, Y., Popiel, H. A., Okamoto, Y., Yamaguchi, M., and Toda, T. (2008). Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones. J. Biol. Chem. 283, 26188-26197. doi: 10.1074/jbc.M710521200
30. Fujimoto, M., Takaki, E., Hayashi, T., Kitaura, Y., Tanaka, Y., Inouye, S., et al. (2005). Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J. Biol. Chem. 280, 34908-34916. doi: 10.1074/jbc.M506288200
31. Fusco, F. R., Chen, Q., Lamoreaux, W. J., Figueredo-Cardenas, G., Jiao, Y., Coffman, J. A., et al. (1999). Cellular localization of huntingtin in striatal and cortical neurons in rats: lack of correlation with neuronal vulnerability in Huntington's disease. J. Neurosci. 19, 1189-1202.
32. Gardian, G., Browne, S. E., Choi, D.-K., Klivenyi, P., Gregorio, J., Kubilus, J. K., et al. (2005). Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease. J. Biol. Chem. 280, 556-563. doi: 10.1074/jbc.M410210200
33. Goldberg, A. L. (2003). Protein degradation and protection against misfolded or damaged proteins. Nature 426, 895-899. doi: 10.1038/nature02263
34. Gourfinkel-An, I., Cancel, G., Trottier, Y., Devys, D., Tora, L., Lutz, Y., et al. (2004). Differential distribution of the normal and mutated forms of huntingtin in the human brain. Ann. Neurol. 42, 712-719. doi: 10.1002/ana.410420507
35. Graveland, G. A., Williams, R. S., and DiFiglia, M. (1985). Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. Science 227, 770-773. doi: 10.1126/science.3155875
36. Gutekunst, C. A., Li, S. H., Yi, H., Mulroy, J. S., Kuemmerle, S., Jones, R., et al. (1999). Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci. 19, 2522-2534.
37. Hersch, S. M. (2008). PHEND-HD: a safety, tolerability, and biomarker study of phenylbutyrate in symptomatic HD. Neurotherapeutics 5, 363. doi: 10.1016/j.nurt.2007.10.058
38. Hipp, M. S., Patel, C. N., Bersuker, K., Riley, B. E., Kaiser, S. E., Shaler, T. A., et al. (2012). Indirect inhibition of 26S proteasome activity in a cellular model of Huntington's disease. J. Cell Biol. 196, 573-587. doi: 10.1083/jcb.201110093
39. Huang, Q., and Figueiredo-Pereira, M. E. (2010). Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications. Apoptosis 15, 1292-1311. doi: 10.1007/s10495-010-0466-z
40. Inagaki, R., Tagawa, K., Qi, M.-L., Enokido, Y., Ito, H., Tamura, T., et al. (2008). Omi / HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington's disease. Eur. J. Neurosci. 28, 30-40. doi: 10.1111/j.1460-9568.2008.06323.x
41. Jackson, W. S. (2014). Selective vulnerability to neurodegenerative disease: the curious case of prion protein. Dis. Model. Mech. 7, 21-29. doi: 10.1242/dmm.012146
42. Jana, N. R., Dikshit, P., Goswami, A., Kotliarova, S., Murata, S., Tanaka, K., et al. (2005). Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J. Biol. Chem.280, 11635-11640. doi: 10.1074/jbc.M412042200
43. Jana, N. R., Zemskov, E. A., Wang, G. H., and Nukina, N. (2001). Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum. Mol. Genet. 10, 1049-1059. doi: 10.1093/hmg/10.10.1049
44. Kieburtz, K., MacDonald, M., Shih, C., Feigin, A., Steinberg, K., Bordwell, K., et al. (1994). Trinucleotide repeat length and progression of illness in Huntington's disease. J. Med. Genet. 31, 872-874. doi: 10.1136/jmg.31.11.872
45. Kim, M., Lee, H. S., LaForet, G., McIntyre, C., Martin, E. J., Chang, P., et al. (1999). Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J. Neurosci.19, 964-973.
46. Klement, I. A., Skinner, P. J., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., et al. (1998). Ataxin-1 nuclear localization and aggregation. Cell 95, 41-53. doi: 10.1016/S0092-8674(00)81781-X
47. Kondrashov, N., Pusic, A., Stumpf, C. R., Shimizu, K., Hsieh, A. C., Xue, S., et al. (2011). Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell 145, 383-397. doi: 10.1016/j.cell.2011.03.028
48. Krobitsch, S., and Lindquist, S. (2000). Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc. Natl. Acad. Sci. U.S.A. 97, 1589-1594. doi: 10.1073/pnas.97.4.1589
49. Kuemmerle, S., Gutekunst, C. A., Klein, A. M., Li, X. J., Li, S. H., Beal, M. F., et al. (1999). Huntington aggregates may not predict neuronal death in Huntington's disease. Ann. Neurol. 46, 842-849. doi: 10.1002/1531-8249(199912)46:6<842::AID-ANA6>3.0.CO;2-O
50. Labbadia, J., Cunliffe, H., Weiss, A., Katsyuba, E., Sathasivam, K., Seredenina, T., et al. (2011). Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease.J. Clin. Invest. 121, 3306. doi: 10.1172/JCI57413DS1
51. Le Grand, J. N., Bon, K., Fraichard, A., Zhang, J., Jouvenot, M., Risold, P.-Y., et al. (2013). Specific distribution of the autophagic protein GABARAPL1/GEC1 in the developing and adult mouse brain and identification of neuronal populations expressing GABARAPL1/GEC1. PLoS ONE 8:e63133. doi: 10.1371/journal.pone.0063133.t001
52. Levine, M. S., Klapstein, G. J., Koppel, A., Gruen, E., Cepeda, C., Vargas, M. E., et al. (1999). Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. J. Neurosci. Res. 58, 515-532. doi: 10.1002/(SICI)1097-4547(19991115)58:4<515::AID-JNR5>3.0.CO;2-F
53. Li, B., Hu, Q., Wang, H., Man, N., Ren, H., Wen, L., et al. (2010). Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases. Cell Death Differ. 17, 1773-1784. doi: 10.1038/cdd.2010.55
54. Liu, X., Miller, B. R., Rebec, G. V., and Clemmer, D. E. (2007). Protein expression in the striatum and cortex regions of the brain for a mouse model of Huntington's disease. J. Proteome Res. 6, 3134-3142. doi: 10.1021/pr070092s
55. Lunkes, A., Lindenberg, K. S., Ben-Haïem, L., Weber, C., Devys, D., Landwehrmeyer, G. B., et al. (2002). Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell 10, 259-269. doi: 10.1016/S1097-2765(02)00602-0
56. Ma, T. C., Buescher, J. L., Oatis, B., Funk, J. A., Nash, A. J., Carrier, R. L., et al. (2007). Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci. Lett. 411, 98-103. doi: 10.1016/j.neulet.2006.10.039
57. Maat-Schieman, M. L., Dorsman, J. C., Smoor, M. A., Siesling, S., Van Duinen, S. G., Verschuuren, J. J., et al. (1999). Distribution of inclusions in neuronal nuclei and dystrophic neurites in Huntington disease brain. J. Neuropathol. Exp. Neurol. 58, 129-137. doi: 10.1097/00005072-199902000-00003
58. Miller, J., Arrasate, M., Shaby, B. A., Mitra, S., Masliah, E., and Finkbeiner, S. (2010). Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into huntington's disease molecular pathogenesis. J. Neurosci. 30, 10541-10550. doi: 10.1523/JNEUROSCI.0146-10.2010
59. Mitra, S., and Finkbeiner, S. (2008). The ubiquitin-proteasome pathway in Huntington's disease. ScientificWorldJournal 8, 421-433. doi: 10.1100/tsw.2008.60
60. Mitra, S., Tsvetkov, A. S., and Finkbeiner, S. (2009). Single neuron ubiquitin-proteasome dynamics accompanying inclusion body formation in huntington disease. J. Biol. Chem. 284, 4398-4403. doi: 10.1074/jbc.M806269200
61. Muchowski, P. J., Schaffar, G., Sittler, A., Wanker, E. E., Hayer-Hartl, M. K., and Hartl, F. U. (2000). Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. U.S.A. 97, 7841-7846. doi: 10.1073/pnas.140202897
62. Muchowski, P. J., and Wacker, J. L. (2005). Modulation of neurodegeneration by molecular chaperones. Nat. Rev. Neurosci. 6, 11-22. doi: 10.1038/nrn1587
63. Neef, D. W., Jaeger, A. M., and Thiele, D. J. (2011). Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat. Rev. Drug Discov. 10, 930-944. doi: 10.1038/nrd3453
64. Neef, D. W., Turski, M. L., and Thiele, D. J. (2010). Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol. 8:e1000291. doi: 10.1371/journal.pbio.1000291
65. Okamoto, S.-I., Pouladi, M. A., Talantova, M., Yao, D., Xia, P., Ehrnhoefer, D. E., et al. (2009). Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat. Med. 15, 1407-1413. doi: 10.1038/nm.2056
66. Oliveira, J. M. A., and Gonçalves, J. (2009). In situ mitochondrial Ca2+ buffering differences of intact neurons and astrocytes from cortex and striatum. J. Biol. Chem. 284, 5010-5020. doi: 10.1074/jbc.M807459200
67. Olzscha, H., Schermann, S. M., Woerner, A. C., Pinkert, S., Hecht, M. H., Tartaglia, G. G., et al. (2011). Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144, 67-78. doi: 10.1016/j.cell.2010.11.050
68. Otabe, H., Nibuya, M., Shimazaki, K., Toda, H., Suzuki, G., Nomura, S., et al. (2014). Electroconvulsive seizures enhance autophagy signaling in rat hippocampus. Prog. Neuropsychopharmacol. Biol. Psychiatry 50, 37-43. doi: 10.1016/j.pnpbp.2013.11.012
69. Pickart, C. M., and Cohen, R. E. (2004). Proteasomes and their kin: proteases in the machine age. Nat. Rev. Mol. Cell Biol. 5, 177-187. doi: 10.1038/nrm1336
70. Pickart, C. M., and Fushman, D. (2004). Polyubiquitin chains: polymeric protein signals. Curr. Opin. Chem. Biol. 8, 610-616. doi: 10.1016/j.cbpa.2004.09.009
71. Poirier, M. A., Jiang, H., and Ross, C. A. (2005). A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure. Hum. Mol. Genet. 14, 765-774. doi: 10.1093/hmg/ddi071
72. Qin, Z.-H., Wang, Y., Kegel, K. B., Kazantsev, A., Apostol, B. L., Thompson, L. M., et al. (2003). Autophagy regulates the processing of amino terminal huntingtin fragments. Hum. Mol. Genet. 12, 3231-3244. doi: 10.1093/hmg/ddg346
73. Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585-595. doi: 10.1038/ng1362
74. Robinson, P., Lebel, M., and Cyr, M. (2008). Dopamine D1 receptor-mediated aggregation of N-terminal fragments of mutant huntingtin and cell death in a neuroblastoma cell line. Neuroscience 153, 762-772. doi: 10.1016/j.neuroscience.2008.02.052
75. Rose, C., Menzies, F. M., Renna, M., Acevedo-Arozena, A., Corrochano, S., Sadiq, O., et al. (2010). Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease. Hum. Mol. Genet. 19, 2144-2153. doi: 10.1093/hmg/ddq093
76. Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O., and Klionsky, D. J. (2007). Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov. 6, 304-312. doi: 10.1038/nrd2272
77. Sarkar, S., Floto, R. A., Berger, Z., Imarisio, S., Cordenier, A., Pasco, M., et al. (2005). Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101-1111. doi: 10.1083/jcb.200504035
78. Sarkar, S., Ravikumar, B., Floto, R. A., and Rubinsztein, D. C. (2009). Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 16, 46-56. doi: 10.1038/cdd.2008.110
79. Saudou, F., Finkbeiner, S., Devys, D., and Greenberg, M. E. (1998). Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55-66. doi: 10.1016/S0092-8674(00)81782-1
80. Seo, H., Sonntag, K.-C., Kim, W., Cattaneo, E., and Isacson, O. (2007). Proteasome activator enhances survival of Huntington's disease neuronal model cells. PLoS ONE 2:e238. doi: 10.1371/journal.pone.0000238.g004
81. Sepe, S., Nardacci, R., Fanelli, F., Rosso, P., Bernardi, C., Cecconi, F., et al. (2014). Expression of Ambra1 in mouse brain during physiological and Alzheimer type aging. Neurobiol. Aging 35, 96-108. doi: 10.1016/j.neurobiolaging.2013.07.001
82. Shehata, M., Matsumura, H., Okubo-Suzuki, R., Ohkawa, N., and Inokuchi, K. (2012). Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J. Neurosci. 32, 10413-10422. doi: 10.1523/JNEUROSCI.4533-11.2012
83. Shibata, M., Lu, T., Furuya, T., Degterev, A., Mizushima, N., Yoshimori, T., et al. (2006). Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474-14485. doi: 10.1074/jbc.M600364200
84. Sieradzan, K. A., and Mann, D. (2001). The selective vulnerability of nerve cells in Huntington's disease. Neuropathol. Appl. Neurobiol. 27, 1-21. doi: 10.1046/j.0305-1846.2001.00299.x
85. Sieradzan, K. A., Mechan, A. O., Jones, L., Wanker, E. E., Nukina, N., and Mann, D. M. (1999). Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp. Neurol. 156, 92-99. doi: 10.1006/exnr.1998.7005
86. Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M. K., et al. (2001). Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum. Mol. Genet. 10, 1307-1315. doi: 10.1093/hmg/10.12.1307
87. Sõti, C., Nagy, E., Giricz, Z., Vígh, L., Csermely, P., and Ferdinandy, P. (2005). Heat shock proteins as emerging therapeutic targets. Br. J. Pharmacol. 146, 769-780. doi: 10.1038/sj.bjp.0706396
88. Steffan, J. S., Agrawal, N., Pallos, J., Rockabrand, E., Trotman, L. C., Slepko, N., et al. (2004). SUMO modification of Huntingtin and Huntington's disease pathology. Science 304, 100-104. doi: 10.1126/science.1092194
89. Stenoien, D. L., Cummings, C. J., Adams, H. P., Mancini, M. G., Patel, K., DeMartino, G. N., et al. (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. Hum. Mol. Genet. 8, 731-741. doi: 10.1093/hmg/8.5.731
90. Tagawa, K., Hoshino, M., Okuda, T., Ueda, H., Hayashi, H., Engemann, S., et al. (2004). Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein. J. Neurochem. 89, 974-987. doi: 10.1111/j.1471-4159.2004.02372.x
91. Tagawa, K., Marubuchi, S., Qi, M.-L., Enokido, Y., Tamura, T., Inagaki, R., et al. (2007). The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes. J. Neurosci. 27, 868-880. doi: 10.1523/JNEUROSCI.4522-06.2007
92. Tai, H.-C., Besche, H., Goldberg, A. L., and Schuman, E. M. (2010). Characterization of the brain 26S proteasome and its interacting proteins. Front. Mol. Neurosci. 3:12. doi: 10.3389/fnmol.2010.00012
93. Tanaka, M., Machida, Y., Niu, S., Ikeda, T., Jana, N. R., Doi, H., et al. (2004). Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat. Med. 10, 148-154. doi: 10.1038/nm985
94. Tang, T.-S., Chen, X., Liu, J., and Bezprozvanny, I. (2007). Dopaminergic signaling and striatal neurodegeneration in Huntington's disease. J. Neurosci. 27, 7899-7910. doi: 10.1523/JNEUROSCI.1396-07.2007
95. Tang, T.-S., Slow, E., Lupu, V., Stavrovskaya, I. G., Sugimori, M., Llinás, R., et al. (2005). Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc. Natl. Acad. Sci. U.S.A. 102, 2602-2607. doi: 10.1073/pnas.0409402102
96. Tebbenkamp, A. T. N., and Borchelt, D. R. (2010). Analysis of chaperone mRNA expression in the adult mouse brain by meta analysis of the allen brain atlas. PLoS ONE 5:e13675. doi: 10.1371/journal.pone.0013675
97. Thakur, A. K., and Wetzel, R. (2002). Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl. Acad. Sci. U.S.A. 99, 17014-17019. doi: 10.1073/pnas.252523899
98. Thomas, E. A. (2006). Striatal specificity of gene expression dysregulation in Huntington's disease. J. Neurosci. Res. 84, 1151-1164. doi: 10.1002/jnr.21046
99. Tsai, Y. C., Fishman, P. S., Thakor, N. V., and Oyler, G. A. (2003). Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J. Biol. Chem. 278, 22044-22055. doi: 10.1074/jbc.M212235200
100. Tsvetkov, A. S., Arrasate, M., Barmada, S., Ando, D. M., Sharma, P., Shaby, B. A., et al. (2013). Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat. Chem. Biol. 9, 586-592. doi: 10.1038/nchembio.1308
101. Tsvetkov, A. S., Miller, J., Arrasate, M., Wong, J. S., Pleiss, M. A., and Finkbeiner, S. (2010). A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc. Natl. Acad. Sci. U.S.A. 107, 16982-16987. doi: 10.1073/pnas.1004498107
102. Vacher, C., Oroz, L. G., and Rubinsztein, D. C. (2005). Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease. Hum. Mol. Genet. 14, 3425-3433. doi: 10.1093/hmg/ddi372
103. Vonsattel, J. P., and DiFiglia, M. (1998). Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369-384. doi: 10.1097/00005072-199805000-00001
104. Vonsattel, J. P., Myers, R. H., Stevens, T. J., Ferrante, R. J., Bird, E. D., and Richardson, E. P. (1985). Neuropathological classification of Huntington's disease. J. Neuropathol. Exp. Neurol. 44, 559-577. doi: 10.1097/00005072-198511000-00003
105. Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M., and Muchowski, P. J. (2004). Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat. Struct. Mol. Biol. 11, 1215-1222. doi: 10.1038/nsmb860
106. Wade, B. E., Wang, C.-E., Yan, S., Bhat, K., Huang, B., Li, S., et al. (2014). Ubiquitin-activating enzyme activity contributes to differential accumulation of mutant huntingtin in brain and peripheral tissues. J. Neurosci. 34, 8411-8422. doi: 10.1523/JNEUROSCI.0775-14.2014
107. Waelter, S., Boeddrich, A., Lurz, R., Scherzinger, E., Lueder, G., Lehrach, H., et al. (2001). Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol. Biol. Cell 12, 1393-1407. doi: 10.1091/mbc.12.5.1393
108. Warrick, J. M., Chan, H. Y. E., Gray-Board, G. L., Chai, Y., Paulson, H. L., and Bonini, N. M. (1999). Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23, 425-428. doi: 10.1038/70532
109. Westerheide, S. D., and Morimoto, R. I. (2005). Heat shock response modulators as therapeutic tools for diseases of protein conformation. J. Biol. Chem. 280, 33097-33100. doi: 10.1074/jbc.R500010200
110. Williams, A., Sarkar, S., Cuddon, P., Ttofi, E. K., Saiki, S., Siddiqi, F. H., et al. (2008). Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol. 4, 295-305. doi: 10.1038/nchembio.79
111. Wyttenbach, A., Carmichael, J., Swartz, J., Furlong, R. A., Narain, Y., Rankin, J., et al. (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. U.S.A. 97, 2898-2903. doi: 10.1073/pnas.97.6.2898
112. Yamamoto, A., Lucas, J. J., and Hen, R. (2000). Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57-66. doi: 10.1016/S0092-8674(00)80623-6
113. Yang, H., Zhong, X., Ballar, P., Luo, S., Shen, Y., Rubinsztein, D. C., et al. (2007). Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin. Exp. Cell Res. 313, 538-550. doi: 10.1016/j.yexcr.2006.10.031
114. Zeron, M. M., Hansson, O., Chen, N., Wellington, C. L., Leavitt, B. R., Brundin, P., et al. (2002). Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33, 849-860. doi: 10.1016/S0896-6273(02)00615-3
115. Zhang, L., Yu, J., Pan, H., Hu, P., Hao, Y., Cai, W., et al. (2007). Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc. Natl. Acad. Sci. U.S.A. 104, 19023-19028. doi: 10.1073/pnas.0709695104
116. Zhou, H., Cao, F., Wang, Z., Yu, Z.-X., Nguyen, H. P., Evans, J., et al. (2003). Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J. Cell Biol. 163, 109-118. doi: 10.1083/jcb.200306038