A current pharmacologic agent versus the promise of next generation therapeutics to ameliorate protein misfolding and/or aggregation diseases

Current Opinion in Chemical Biology

Volumn 32, Issue , 2016, Pages 10-21

  Baranczak, Aleksandra ^a   Kelly, Jeffery W ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID; AMYLOID BETA PROTEIN; AMYLOID PROTEIN; APOLIPOPROTEIN A1; BENZOXAZOLE DERIVATIVE; CARBOXYLIC ACID; CHAPERONE; HEAT SHOCK PROTEIN 70; HEAT SHOCK PROTEIN 90; INTRINSICALLY DISORDERED PROTEIN; MONOMER; NONSTEROID ANTIINFLAMMATORY AGENT; PHOSPHATASE; PLACEBO; PREALBUMIN; PROTEASOME; RETINOID BINDING PROTEIN; TAFAMIDIS; TETRAMER; THYROXINE;

ALZHEIMER DISEASE; AMYLOIDOGENESIS; AMYLOIDOSIS; AMYOTROPHIC LATERAL SCLEROSIS; CARDIOMYOPATHY; CRYSTAL STRUCTURE; DEGENERATIVE DISEASE; FAMILIAL AMYLOID CARDIOMYOPATHY; FAMILIAL AMYLOID POLYNEUROPATHY; GENE THERAPY; HEAT SHOCK RESPONSE; HUMAN; LIVER TRANSPLANTATION; MOLECULARLY TARGETED THERAPY; MUTANT; NEXT GENERATION SEQUENCING; NONHUMAN; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POLYMERIZATION; PROTEIN AGGREGATION; PROTEIN ASSEMBLY; PROTEIN FOLDING; PROTEIN HOMEOSTASIS; PROTEIN MISFOLDING; PROTEIN STABILITY; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; UNFOLDED PROTEIN RESPONSE; VIRUS INFECTION; WILD TYPE; PROTEOSTASIS DEFICIENCIES;

HUMANS; PROTEIN FOLDING; PROTEOSTASIS DEFICIENCIES;

EID: 84957103451     PISSN: 13675931     EISSN: 18790402     Source Type: Journal    
DOI: 10.1016/j.cbpa.2016.01.009     Document Type: Review

References (124)

1. Kelly J.W. The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. Curr Opin Struct Biol 1998, 8:101-106.
2. Eisele Y.S., Monteiro C., Fearns C., Encalada S.E., Wiseman R.L., Powers E.T., Kelly J.W. Targeting protein aggregation for the treatment of degenerative diseases. Nat Rev Drug Discovery 2015, 14:759-780.
3. Knowles T.P., Vendruscolo M., Dobson C.M. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 2014, 15:384-396.
4. Nelson R., Sawaya M.R., Balbirnie M., Madsen A.O., Riekel C., Grothe R., Eisenberg D. Structure of the cross-beta spine of amyloid-like fibrils. Nature 2005, 435:773-778.
5. Laganowsky A., Liu C., Sawaya M.R., Whitelegge J.P., Park J., Zhao M.L., Pensalfini A., Soriaga A.B., Landau M., Teng P.K., et al. Atomic view of a toxic amyloid small oligomer. Science 2012, 335:1228-1231.
6. Eisenberg D., Jucker M. The amyloid state of proteins in human diseases. Cell 2012, 148:1188-1203.
7. Caughey B., Lansbury P.T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 2003, 26:267-298.
8. Arrasate M., Mitra S., Schweitzer E.S., Segal M.R., Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004, 431:805-810.
9. Bourgault S., Solomon J.P., Reixach N., Kelly J.W. Sulfated glycosaminoglycans accelerate transthyretin amyloidogenesis by quaternary structural conversion. Biochemistry 2011, 50:1001-1015.
10. Pepys M.B., Herbert J., Hutchinson W.L., Tennent G.A., Lachmann H.J., Gallimore J.R., Lovat L.B., Bartfai T., Alanine A., Hertel C., et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 2002, 417:254-259.
11. Chiti F., Stefani M., Taddei N., Ramponi G., Dobson C.M. Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature 2003, 424:805-808.
12. Sekijima Y., Wiseman R.L., Matteson J., Hammarstrom P., Miller S.R., Sawkar A.R., Balch W.E., Kelly J.W. The biological and chemical basis for tissue-selective amyloid disease. Cell 2005, 121:73-85.
13. Ben-Zvi A., Miller E.A., Morimoto R.I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc Natl Acad Sci U S A 2009, 106:14914-14919.
14. Haigis M.C., Yankner B.A. The aging stress response. Mol Cell 2010, 40:333-344.
15. Cuanalo-Contreras K., Mukherjee A., Soto C. Role of protein misfolding and proteostasis deficiency in protein misfolding diseases and aging. Int J Cell Biol 2013, 2013:638083.
16. Cohen F.E., Kelly J.W. Therapeutic approaches to protein-misfolding diseases. Nature 2003, 426:905-909.
17. Miroy G.J., Lai Z., Lashuel H.A., Peterson S.A., Strang C., Kelly J.W. Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc Natl Acad Sci U S A 1996, 93:15051-15056.
18. Hammarstrom P., Jiang X., Hurshman A.R., Powers E.T., Kelly J.W. Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A 2002, 99(Suppl. 4):16427-16432.
19. Hammarstrom P., Wiseman R.L., Powers E.T., Kelly J.W. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 2003, 299:713-716.
20. Schreiber G., Richardson S.J. The evolution of gene expression, structure and function of transthyretin. Comp Biochem Physiol B Biochem Mol Biol 1997, 116:137-160.
21. Herbert J., Wilcox J.N., Pham K.T.C., Fremeau R.T., Zeviani M., Dwork A., Soprano D.R., Makover A., Goodman D.S., Zimmerman E.A., et al. Transthyretin - a choroid plexus-specific transport protein in human brain. Neurology 1986, 36:900-911.
22. Cavallaro T., Martone R.L., Dwork A.J., Schon E.A., Herbert J. The retinal pigment epithelium is the unique site of transthyretin synthesis in the rat eye. Invest Ophthalmol Vis Sci 1990, 31:497-501.
23. Blake C.C., Geisow M.J., Oatley S.J., Rerat B., Rerat C. Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 Å. J Mol Biol 1978, 121:339-356.
24. Foss T.R., Kelker M.S., Wiseman R.L., Wilson I.A., Kelly J.W. Kinetic stabilization of the native state by protein engineering: implications for inhibition of transthyretin amyloidogenesis. J Mol Biol 2005, 347:841-854.
25. Foss T.R., Wiseman R.L., Kelly J.W. The pathway by which the tetrameric protein transthyretin dissociates. Biochemistry 2005, 44:15525-15533.
26. Hurshman Babbes A.R., Powers E.T., Kelly J.W. Quantification of the thermodynamically linked quaternary and tertiary structural stabilities of transthyretin and its disease-associated variants: the relationship between stability and amyloidosis. Biochemistry 2008, 47:6969-6984.
27. Lashuel H.A., Lai Z., Kelly J.W. Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M, and L55P amyloid fibril formation. Biochemistry 1998, 37:17851-17864.
28. Lashuel H.A., Wurth C., Woo L., Kelly J.W. The most pathogenic transthyretin variant, L55P, forms amyloid fibrils under acidic conditions and protofilaments under physiological conditions. Biochemistry 1999, 38:13560-13573.
29. Hurshman A.R., White J.T., Powers E.T., Kelly J.W. Transthyretin aggregation under partially denaturing conditions is a downhill polymerization. Biochemistry 2004, 43:7365-7381.
30. Hammarstrom P., Sekijima Y., White J.T., Wiseman R.L., Lim A., Costello C.E., Altland K., Garzuly F., Budka H., Kelly J.W. D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid: a prescription for central nervous system amyloidosis?. Biochemistry 2003, 42:6656-6663.
31. Jiang X., Buxbaum J.N., Kelly J.W. The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. Proc Natl Acad Sci U S A 2001, 98:14943-14948.
32. Andrade C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 1952, 75:408-427.
33. Cornwell G.G., Sletten K., Johansson B., Westermark P. Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealbumin. Biochem Biophys Res Commun 1988, 154:648-653.
34. Westermark P., Sletten K., Johansson B., Cornwell G.G. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci U S A 1990, 87:2843-2845.
35. Coelho T. Familial amyloid polyneuropathy: new developments in genetics and treatment. Curr Opin Neurol 1996, 9:355-359.
36. Jacobson D.R., McFarlin D.E., Kane I., Buxbaum J.N. Transthyretin Pro55, a variant associated with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement. Hum Genet 1992, 89:353-356.
37. Dharmarajan K., Maurer M.S. Transthyretin cardiac amyloidoses in older north Americans. J Am Geriat Soc 2012, 60:765-774.
38. Falk R.H., Elkayam U. Cardiomyopathy: the importance of recognizing the uncommon diagnosis. Prog Cardiovasc Dis 2010, 52:262-263.
39. Gursky O., Mei X., Atkinson D. The crystal structure of the C-terminal truncated apolipoprotein A-I sheds new light on amyloid formation by the N-terminal fragment. Biochemistry 2012, 51:10-18.
40. Hamidi Asl L., Liepnieks J.J., Hamidi Asl K., Uemichi T., Moulin G., Desjoyaux E., Loire R., Delpech M., Grateau G., Benson M.D. Hereditary amyloid cardiomyopathy caused by a variant apolipoprotein A1. Am J Pathol 1999, 154:221-227.
41. Holmgren G., Ericzon B.G., Groth C.G., Steen L., Suhr O., Andersen O., Wallin B.G., Seymour A., Richardson S., Hawkins P.N. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993, 341:1113-1116.
42. Herlenius G., Wilczek H.E., Larsson M., Ericzon B.G. Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 2004, 77:64-71.
43. Olofsson B.O., Backman C., Karp K., Suhr O.B. Progression of cardiomyopathy after liver transplantation in patients with familial amyloidotic polyneuropathy, Portuguese type. Transplantation 2002, 73:745-751.
44. Coelho T., Carvalho M., Saraiva M.J., Alves I., Almeida M.R., Costa P.P. A strikingly benign evolution of FAP in an individual found to be a compound heterozygote for two TTR mutations: TTR MET 30 and TTR MET 119. J Rheumatol 1993, 20:179.
45. Coelho T., Chorao R., Sausa A., Alves I., Torres M.F., Saraiva M.J. Compound heterozygotes of transthyretin Met30 and transthyretin Met119 are protected from the devastating effects of familial amyloid polyneuropathy. Neuromusc Disord 1996, 6:27.
46. Hammarstrom P., Schneider F., Kelly J.W. Trans-suppression of misfolding in an amyloid disease. Science 2001, 293:2459-2462.
47. Colon W., Kelly J.W. Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 1992, 31:8654-8660.
48. Lai Z., Colon W., Kelly J.W. The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid. Biochemistry 1996, 35:6470-6482.
49. Baures P.W., Oza V.B., Peterson S.A., Kelly J.W. Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid. Bioorg Med Chem 1999, 7:1339-1347.
50. Baures P.W., Peterson S.A., Kelly J.W. Discovering transthyretin amyloid fibril inhibitors by limited screening. Bioorg Med Chem 1998, 6:1389-1401.
51. Klabunde T., Petrassi H.M., Oza V.B., Raman P., Kelly J.W., Sacchettini J.C. Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Biol 2000, 7:312-321.
52. Connelly S., Choi S., Johnson S.M., Kelly J.W., Wilson I.A. Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Curr Opin Struct Biol 2010, 20:54-62.
53. Johnson S.M., Connelly S., Fearns C., Powers E.T., Kelly J.W. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J Mol Biol 2012, 421:185-203.
54. Johnson S.M., Wiseman R.L., Sekijima Y., Green N.S., Adamski-Werner S.L., Kelly J.W. Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses. Acc Chem Res 2005, 38:911-921.
55. Johnson S.M., Connelly S., Wilson I.A., Kelly J.W. Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. J Med Chem 2008, 51:6348-6358.
56. Johnson S.M., Connelly S., Wilson I.A., Kelly J.W. Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors. J Med Chem 2008, 51:260-270.
57. Johnson S.M., Connelly S., Wilson I.A., Kelly J.W. Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. J Med Chem 2009, 52:1115-1125.
58. Razavi H., Palaninathan S.K., Powers E.T., Wiseman R.L., Purkey H.E., Mohamedmohaideen N.N., Deechongkit S., Chiang K.P., Dendle M.T., Sacchettini J.C., et al. Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action. Angew Chem 2003, 42:2758-2761.
59. Sekijima Y., Dendle M.A., Kelly J.W. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 2006, 13:236-249.
60. Choi S., Kelly J.W. A competition assay to identify amyloidogenesis inhibitors by monitoring the fluorescence emitted by the covalent attachment of a stilbene derivative to transthyretin. Bioorg Med Chem 2011, 19:1505-1514.
61. Rappley I., Monteiro C., Novais M., Baranczak A., Solis G., Wiseman R.L., Helmke S., Maurer M.S., Coelho T., Powers E.T., et al. Quantification of transthyretin kinetic stability in human plasma using subunit exchange. Biochemistry 2014, 53:1993-2006.
62. Bulawa C.E., Connelly S., DeVit M., Wang L., Weigel C., Fleming J.A., Packman J., Powers E.T., Wiseman R.L., Foss T.R., et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A 2012, 109. 9629-9634, S9629/9621-S9629/9629.
63. Wiseman R.L., Johnson S.M., Kelker M.S., Foss T., Wilson I.A., Kelly J.W. Kinetic stabilization of an oligomeric protein by a single ligand binding event. J Am Chem Soc 2005, 127:5540-5551.
64. Coelho T., Maia L., Martins da Silva A., Waddington Cruz M., Planté-Bordeneuve V., Lozeron P., Suhr O.B., Campistol J.M., Conceição I., Schmidt H.H.-J., et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012, 79:785-792.
65. Coelho T., Maia L.F., da Silva A.M., Cruz M.W., Plante-Bordeneuve V., Suhr O.B., Conceicao I., Schmidt H.H.J., Trigo P., Kelly J.W., et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 2013, 260:2802-2814.
66. Maurer M.S., Grogan D.R., Judge D.P., Mundayat R., Packman J., Lombardo I., Quyyumi A.A., Aarts J., Falk R.H. Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes. Circ Heart Fail 2015, 8:519-526.
67. Balch W.E., Morimoto R.I., Dillin A., Kelly J.W. Adapting proteostasis for disease intervention. Science 2008, 319:916-919.
68. Powers E.T., Morimoto R.I., Dillin A., Kelly J.W., Balch W.E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 2009, 78:959-991.
69. Hartl F.U., Bracher A., Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature 2011, 475:324-332.
70. Morimoto R.I. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 1998, 12:3788-3796.
71. Lindquist S. The heat shock response. Annu Rev Biochem 1986, 55:1151-1191.
72. Ron D., Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007, 8:519-529.
73. Schroder M., Kaufman R.J. The mammalian unfolded protein response. Ann Rev Biochem 2005, 74:739-789.
74. Guisbert E., Morimoto R.I. The regulation and function of the heat shock response. Protein Qualtiy Control in Neurodegenerative Diseases. Research and Perspectives in Alzheimer's Disease 2013, 1-18. Springer-Verlag Berlin Heidelberg. R.I. Morimoto, Y. Christen (Eds.).
75. Ryno L.M., Wiseman R.L., Kelly J.W. Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases. Curr Opin Chem Biol 2013, 17:346-352.
76. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 2012, 13:89-102.
77. Shoulders M.D., Ryno L.M., Cooley C.B., Kelly J.W., Wiseman R.L. Broadly applicable methodology for the rapid and dosable small molecule-mediated regulation of transcription factors in human cells. J Am Chem Soc 2013, 135:8129-8132.
78. Shoulders M.D., Ryno L.M., Genereux J.C., Moresco J.J., Tu P.G., Wu C.L., Yates J.R., Su A.I., Kelly J.W., Wiseman R.L. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 2013, 3:1279-1292.
79. Calamini B., Silva M.C., Madoux F., Hutt D.M., Khanna S., Chalfant M.A., Saldanha S.A., Hodder P., Tait B.D., Garza D., et al. Small-molecule proteostasis regulators for protein conformational diseases. Nat Chem Biol 2012, 8:185-196.
80. Wang A.M., Miyata Y., Klinedinst S., Peng H.M., Chua J.P., Komiyama T., Li X.K., Morishima Y., Merry D.E., Pratt W.B., et al. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol 2013, 9:112-118.
81. Pratt W.B., Gestwicki J.E., Osawa Y., Lieberman A.P. Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases. Annu Rev Pharmacol Toxicol 2015, 55:353-371.
82. Chafekar S.M., Wisen S., Thompson A.D., Echeverria A., Walter G.M., Evans C.G., Makley L.N., Gestwicki J.E., Duennwald M.L. Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation. ACS Chem Biol 2012, 7:1556-1564.
83. Jinwal U.K., Akoury E., Abisambra J.F., O'Leary J.C., Thompson A.D., Blair L.J., Jin Y., Bacon J., Nordhues B.A., Cockman M., et al. Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J 2013, 27:1450-1459.
84. Miyata Y., Li X.K., Lee H.F., Jinwal U.K., Srinivasan S.R., Seguin S.P., Young Z.T., Brodsky J.L., Dickey C.A., Sun D.X., et al. Synthesis and initial evaluation of YM-08, a blood-brain barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-077, which reduces tau levels. ACS Chem Neurosci 2013, 4:930-939.
85. Smith M.C., Scaglione K.M., Assimon V.A., Patury S., Thompson A.D., Dickey C.A., Southworth D.R., Paulson H.L., Gestwicki J.E., Zuiderweg E.R.P. The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry 2013, 52:5354-5364.
86. Hetz C., Mollereau B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 2014, 15:233-249.
87. Lamech L.T., Haynes C.M. The unpredictability of prolonged activation of stress response pathways. J Cell Biol 2015, 209:781-787.
88. Narayan P., Ehsani S., Lindquist S. Combating neurodegenerative disease with chemical probes and model systems. Nat Chem Biol 2014, 10:911-920.
89. Taylor R.C., Dillin A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 2013, 153:1435-1447.
90. Cohen E., Bieschke J., Perciavalle R.M., Kelly J.W., Dillin A. Opposing activities protect against age-onset proteotoxicity. Science 2006, 313:1604-1610.
91. Das I., Krzyzosiak A., Schneider K., Wrabetz L., D'Antonio M., Barry N., Sigurdardottir A., Bertolotti A. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 2015, 348:239-242.
92. Mu T.W., Ong D.S.T., Wang Y.J., Balch W.E., Yates J.R., Segatori L., Kelly J.W. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 2008, 134:769-781.
93. Hulleman J.D., Balch W.E., Kelly J.W. Translational attenuation differentially alters the fate of disease-associated fibulin proteins. FASEB J 2012, 26:4548-4560.
94. Chiang W.C., Messah C., Lin J.H. IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin. Mol Biol Cell 2012, 23:758-770.
95. Cooley C.B., Ryno L.M., Plate L., Morgan G.J., Hulleman J.D., Kelly J.W., Wiseman L.R. Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic light chain. Proc Natl Acad Sci U S A 2014, 111:13046-13051.
96. Smith S.E., Granell S., Salcedo-Sicilia L., Baldini G., Egea G., Teckman J.H., Baldini G. Activating transcription factor 6 limits intracellular accumulation of mutant alpha(1)-antitrypsin Z and mitochondrial damage in hepatoma cells. J Biol Chem 2011, 286:41563-41577.
97. Wang S., Kaufman R.J. The impact of the unfolded protein response on human disease. J Cell Biol 2012, 197:857-867.
98. Genereux J.C., Qu S., Zhou M., Ryno L.M., Wang S., Shoulders M.D., Kaufman R.J., Lasmezas C.I., Kelly J.W., Wiseman R.L. Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J 2015, 34:4-19.
99. Jimenez-Sanchez M., Lam W., Hannus M., Sonnichsen B., Imarisio S., Fleming A., Tarditi A., Menzies F., Ed Dami T., Xu C., et al. siRNA screen identifies QPCT as a druggable target for Huntington's disease. Nat Chem Biol 2015, 11:347-354.
100. Ciechanover A., Kwon Y.T. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 2015, 47:e147.
101. King R.W., Finley D. Sculpting the proteome with small molecules. Nat Chem Biol 2014, 10:870-874.
102. Rubinsztein D.C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006, 443:780-786.
103. Mizushima N., Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011, 147:728-741.
104. Cuervo A.M., Stefanis L., Fredenburg R., Lansbury P.T., Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004, 305:1292-1295.
105. Manchon J.F.M., Uzor N.E., Dabaghian Y., Furr-Stimming E.E., Finkbeiner S., Tsvetkov A.S. Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy. Sci Rep 2015, 5.
106. Schneider J.L., Cuervo A.M. Autophagy and human disease: emerging themes. Curr Opin Genet Dev 2014, 26:16-23.
107. Quiros P.M., Langer T., Lopez-Otin C. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol 2015, 16:345-359.
108. Villella A.T., Malhotra J., Bhalla A., Nokes E., Hurtado-Lorenzo A., Calamani B., Soper J., Gao B.B., Giuliano K., Hafiz M., et al. Inhibition of Usp14 stimulates the proteolytic degradation and clearance of misfolded proteins associated with neurodegenerative diseases. FASEB J 2013, 27.
109. Lee B.H., Lee M.J., Park S., Oh D.C., Elsasser S., Chen P.C., Gartner C., Dimova N., Hanna J., Gygi S.P., et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 2010, 467. 179-U163.
110. Karuppagounder S.S., Brahmachari S., Lee Y., Dawson V.L., Dawson T.M., Ko H.S. The c-Abl inhibitor, Nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Sci Rep 2014, 4.
111. Hebron M.L., Lonskaya I., Moussa C.E.H. Tyrosine kinase inhibition facilitates autophagic SNCA/alpha-synuclein clearance. Autophagy 2013, 9:1249-1250.
112. Mahul-Mellier A.L., Fauvet B., Gysbers A., Dikiy I., Oueslati A., Georgeon S., Lamontanara A.J., Bisquertt A., Eliezer D., Masliah E., et al. c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson's disease. Hum Mol Genet 2014, 23:2858-2879.
113. Tanabe A., Yamamura Y., Kasahara J., Morigaki R., Kaji R., Goto S. A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson's disease. Front Cell Neurosci 2014, 8.
114. Gan-Or Z., Dion P.A., Rouleau G.A. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 2015, 11:1443-1457.
115. Lu Y.H., Yuan X.D., Sun Q.Y., Ou Y. Autophagy activator promotes neuronal differentiation of adult adipose-derived stromal cells. Neural Regen Res 2013, 8:882-889.
116. Wang Z.H., Ren W.Y., Zhu L., Hu L.J. Plasminogen activator inhibitor-1 regulates LPS induced inflammation in rat macrophages through autophagy activation. Sci World J 2014.
117. Wong V.K.W., Ko C.B., Law Y.K. TRI001 is a novel activator of autophagy via MTOR-dependent mechanisms. Eur J Cancer 2013, 49. S4.
118. Ge D., Han L., Huang S.Y., Peng N., Wang P.C., Jiang Z., Zhao J., Su L., Zhang S.L., Zhang Y., et al. Identification of a novel MTOR activator and discovery of a competing endogenous RNA regulating autophagy in vascular endothelial cells. Autophagy 2014, 10:957-971.
119. Liu Y.Q., Cheng X., Guo L.X., Mao C., Chen Y.J., Liu H.X., Xiao Q.C., Jiang S., Yao Z.J., Zhou G.B. Identification of an annonaceous acetogenin mimetic, AA005, as an AMPK activator and autophagy inducer in colon cancer cells. PLoS One 2012, 7.
120. Vingtdeux V., Chandakkar P., Zhao H.T., d'Abramo C., Davies P., Marambaud P. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J 2011, 25:219-231.
121. Wang I.F., Guo B.S., Liu Y.C., Wu C.C., Yang C.H., Tsai K.J., Shen C.K.J. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci U S A 2012, 109:15024-15029.
122. Yang Y.P., Hu L.F., Zheng H.F., Mao C.J., Hu W.D., Xiong K.P., Wang F., Liu C.F. Application and interpretation of current autophagy inhibitors and activators. Acta Pharm Sin 2013, 34:625-635.
123. Efeyan A., Comb W.C., Sabatini D.M. Nutrient-sensing mechanisms and pathways. Nature 2015, 517:302-310.
124. Kang S.A., Pacold M.E., Cervantes C.L., Lim D., Lou H.J., Ottina K., Gray N.S., Turk B.E., Yaffe M.B., Sabatini D.M. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 2013, 341:1236566.