![]() ![]() J Mol Biol 425:4614–4628ĭedmon MM, Christodoulou J, Wilson MR, Dobson CM (2005) Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. Hum Mol Genet 10:1511–1518ĭaturpalli S, Waudby CA, Meehan S, Jackson SE (2013) Hsp90 inhibits α-synuclein aggregation by interacting with soluble oligomers. Nat Genet 19:148–154Ĭummings CJ et al (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Neuron 101:1057–1069Ĭummings CJ et al (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Struct Mol Biol 22:207–213Ĭook C, Petrucelli L (2019) Genetic convergence brings clarity to the enigmatic red line in ALS. Hum Mol Genet 9:2811–2820Ĭohen SIA et al (2015) A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. J Neurosci 19:10338–10347Ĭhan HYE, Warrick JM, Gray-Board GL, Paulson HL, Bonini NM (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mutat 37:1202–1208Ĭhai Y, Koppenhafer SL, Bonini NM, Paulson HL (1999) Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. Histochem Cell Biol 118:353–360Ĭapponi S et al (2016) Molecular chaperones in the pathogenesis of amyotrophic lateral sclerosis: the role of HSPB1. Nature 416:507–511īückig A, Tikkanen R, Herzog V, Schmitz A (2002) Cytosolic and nuclear aggregation of the amyloid β-peptide following its expression in the endoplasmic reticulum. Cell Rep 9:1–16īucciantini M et al (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. J Clin Invest 123:4158–4169īrehme M et al (2014) A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. J Neurosci 26:8160–8167īlair LJ et al (2013) Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. ![]() J Biol Chem 280:2873–2878īaglioni S et al (2006) Prefibrillar amyloid aggregates could be generic toxins in higher organisms. Science 295:865–868Īuluck PK, Meulener MC, Bonini NM (2005) Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in Drosophila. Nat Med 8:1185–1186Īuluck PK, Chan HYE, Trojanowski JQ, Lee VMY, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Nat Commun 7:10948Īuluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Īrosio P et al (2016) Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation. Genes Dev 6:1153–1164Īprile FA et al (2017) Inhibition of α-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α-Synuclein Species. J Neurosci 30:15374 LP–15315382Ībravaya K, Myers MP, Murphy SP, Morimoto RI (1992) The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. KeywordsĪbisambra JF et al (2010) Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal Plasticity Deficits in Tau Transgenic Mice. The phenomenon of chaperone competition may underlie the broad pathology observed in aging and neurodegenerative diseases, and restoration of physiological protein homeostasis may be a suitable therapeutic avenue for neurodegeneration as well as for cancer. In both situations, physiological levels of molecular chaperones eventually become functionally compromised by the persistence of misfolded substrates, leading to a decline in global protein homeostasis and the dysregulation of diverse cellular pathways. In contrast, for cancer cells the upregulation of chaperones has the undesirable effect of promoting cellular survival and tumor growth by stabilizing mutant oncoproteins. Accordingly, overexpression of molecular chaperones and induction of the heat shock response have been shown to be protective in a wide range of animal models of these diseases. For Alzheimer’s, Parkinson’s, Huntington’s diseases and ALS, multiple classes of molecular chaperones interact with the highly aggregation-prone proteins amyloid-β, tau, α-synuclein, huntingtin and SOD1 to influence the course of proteotoxicity associated with these neurodegenerative diseases. Among the critical components of the Proteostasis Network (PN) are molecular chaperones that serve widely in protein biogenesis under physiological conditions, and prevent protein misfolding and aggregation enhanced by conditions of cellular stress. Protein homeostasis (Proteostasis) is essential for correct and efficient protein function within the living cell. ![]()
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