TY - JOUR
T1 - Molecular chaperones and co-chaperones in parkinson disease
AU - Dimant, Hemi
AU - Ebrahimi-Fakhari, Darius
AU - McLean, Pamela J.
N1 - Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Health (grant NS063963) (P.J.M.), the German National Academic Foundation (D.E.-F.), the Hamburg Foundation for International Research and Studies (D.E.-F.), the Parkinson’s Disease Foundation (D.E.-F.), and the Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grants (T32) (H.D.).
PY - 2012/12
Y1 - 2012/12
N2 - Parkinson disease, a progressive neurodegenerative disorder, is caused by the pathological accumulation of proteins, including the ubiquitous presynaptic protein α-synuclein. Alterations in the metabolism of α-synuclein have clearly been linked to neurodegeneration, and early steps in the pathological sequence of this protein include the formation of oligomers, fibrils, and small aggregates. Targeting these early steps of oligomerization is one of the main therapeutic approaches in the quest to develop disease-modifying agents. Molecular chaperones, molecules that can mediate the proper folding and refolding of client proteins, are vital to cell function and survival and thus have been explored as potential therapeutic agents. Important to Parkinson disease, chaperones are capable of preventing α-synuclein misfolding, oligomerization, and aggregate formation as shown in vitro and in Parkinson disease animal models. Furthermore, chaperones and associated co-chaperones are closely linked to pathways of protein degradation, like the ubiquitin-proteasome system and autophagy, and are thus able to remove irreversibly misfolded proteins. In this review, we summarize the role of molecular chaperones in Parkinson disease models and discuss the importance of preserving protein homeostasis to prevent neurodegeneration. We also review the growing number of exciting studies that have targeted molecular chaperone function as a novel therapeutic approach.
AB - Parkinson disease, a progressive neurodegenerative disorder, is caused by the pathological accumulation of proteins, including the ubiquitous presynaptic protein α-synuclein. Alterations in the metabolism of α-synuclein have clearly been linked to neurodegeneration, and early steps in the pathological sequence of this protein include the formation of oligomers, fibrils, and small aggregates. Targeting these early steps of oligomerization is one of the main therapeutic approaches in the quest to develop disease-modifying agents. Molecular chaperones, molecules that can mediate the proper folding and refolding of client proteins, are vital to cell function and survival and thus have been explored as potential therapeutic agents. Important to Parkinson disease, chaperones are capable of preventing α-synuclein misfolding, oligomerization, and aggregate formation as shown in vitro and in Parkinson disease animal models. Furthermore, chaperones and associated co-chaperones are closely linked to pathways of protein degradation, like the ubiquitin-proteasome system and autophagy, and are thus able to remove irreversibly misfolded proteins. In this review, we summarize the role of molecular chaperones in Parkinson disease models and discuss the importance of preserving protein homeostasis to prevent neurodegeneration. We also review the growing number of exciting studies that have targeted molecular chaperone function as a novel therapeutic approach.
KW - Parkinson disease
KW - co-chaperone
KW - heat shock protein (Hsp)
KW - molecular chaperone
KW - neurodegeneration
KW - α-synuclein
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U2 - 10.1177/1073858412441372
DO - 10.1177/1073858412441372
M3 - Review article
C2 - 22829394
AN - SCOPUS:84865861347
SN - 1073-8584
VL - 18
SP - 589
EP - 601
JO - Neuroscientist
JF - Neuroscientist
IS - 6
ER -