Molecular chaperones and neuronal proteostasis - PubMed (original) (raw)

Review

Molecular chaperones and neuronal proteostasis

Heather L Smith et al. Semin Cell Dev Biol. 2015 Apr.

Abstract

Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms.

Keywords: Heat shock response; Molecular chaperone; Neurodegeneration; Neuroprotection; Protein aggregation; Unfolded protein response.

Copyright © 2015 Elsevier Ltd. All rights reserved.

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Figures

Fig. 1

Fig. 1. HSJ1a acts restore proteostasis for several neurodegeneration proteins

Schematic showing the effect of HSJ1a on Htt, SOD1, parkin and tau in neurons. HSJ1a can bind to ubiquitylated oligomers of Htt in the nucleus blocking the recruitment of more misfolded Htt and further aggregation, leading to increases in soluble Htt and potential autophagic clearance of cytoplasmic Htt oligomers [39]. HSJ1 also facilitates proteasomal degradation of Htt [37]. HSJ1a blocks the aggregation of mutant parkin and stimulates its refolding, so that parkin can function in mitochondrial quality control [95]. In ALS, HSJ1a reduces the aggregation of mutant SOD1 and promotes the degradation by proteasome [45]. HSJ1a can bind tau, reduce tau phosphorylation and aggregation (Novoselov and Cheetham unpublished observations).

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References

    1. Ellis J. Proteins as molecular chaperones. Nature. 1987;328:378–379. - PubMed
    1. Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature. 2011;475:324–333. - PubMed
    1. Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu. Rev. Biochem. 2013;82:323–355. - PubMed
    1. Pearl LH, Prodromou C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Ann. Rev. Biochem. 2006;75:271–294. - PubMed
    1. Liberek K, Marszalek J, Ang D, Georgopoulos C, Zylicz M. Escherichia coli DnaJ and GrpE heat shock proteins jointly stimulate ATPase activity of DnaK. Proc. Natl. Acad. Sci. 1991;88:2874–2878. - PMC - PubMed

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