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Molecular chaperones and protein folding as therapeutic targets in Parkinson’s disease and other synucleinopathies

Ebrahimi-Fakhari, Darius ; Saidi, Laiq-Jan ; Wahlster, Lara

In: Acta Neuropathologica Communications, 1 (2013), Nr. 79. pp. 1-15. ISSN 2051-5960

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Abstract

Changes in protein metabolism are key to disease onset and progression in many neurodegenerative diseases. As a prime example, in Parkinson’s disease, folding, post-translational modification and recycling of the synaptic protein α-synuclein are clearly altered, leading to a progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. Altered protein folding is one of the first steps of an increasingly understood cascade in which α-synuclein forms complex oligomers and finally distinct protein aggregates, termed Lewy bodies and Lewy neurites. In neurons, an elaborated network of chaperone and co-chaperone proteins is instrumental in mediating protein folding and re-folding. In addition to their direct influence on client proteins, chaperones interact with protein degradation pathways such as the ubiquitin-proteasome-system or autophagy in order to ensure the effective removal of irreversibly misfolded and potentially pathogenic proteins. Because of the vital role of proper protein folding for protein homeostasis, a growing number of studies have evaluated the contribution of chaperone proteins to neurodegeneration. We herein review our current understanding of the involvement of chaperones, co-chaperones and chaperone-mediated autophagy in synucleinopathies with a focus on the Hsp90 and Hsp70 chaperone system. We discuss genetic and pathological studies in Parkinson’s disease as well as experimental studies in models of synucleinopathies that explore molecular chaperones and protein degradation pathways as a novel therapeutic target. To this end, we examine the capacity of chaperones to prevent or modulate neurodegeneration and summarize the current progress in models of Parkinson’s disease and related neurodegenerative disorders.

Item Type: Article
Journal or Publication Title: Acta Neuropathologica Communications
Volume: 1
Number: 79
Publisher: BioMed Central
Place of Publication: London
Date Deposited: 19 Jan 2016 09:54
Date: 2013
ISSN: 2051-5960
Page Range: pp. 1-15
Faculties / Institutes: Medizinische Fakultät Heidelberg > Universitätskinderklinik
Subjects: 610 Medical sciences Medicine
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