Mutual exacerbation of peroxisome proliferator-activated receptor ? coactivator 1? deregulation and ?-synuclein oligomerization.
Ontology highlight
ABSTRACT: Aggregation of ?-synuclein (?-syn) and ?-syn cytotoxicity are hallmarks of sporadic and familial Parkinson disease (PD), with accumulating evidence that prefibrillar oligomers and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC-1? in mitochondria, no studies have addressed whether PGC-1? directly influences oligomerization of ?-syn or whether ?-syn oligomers impact PGC-1? expression.We tested whether pharmacological or genetic activation of PGC-1? or PGC-11? knockdown could modulate the oligomerization of ?-syn in vitro by using an ?-syn -fragment complementation assay.In this study, we found that both PGC-1? reference gene (RG-PGC-1?) and the central nervous system (CNS)-specific PGC-1? (CNS-PGC-1?) are downregulated in human PD brain, in A30P ?-syn transgenic animals, and in a cell culture model for ?-syn oligomerization. Importantly, downregulation of both RG-PGC-1? and CNS-PGC-1? in cell culture or neurons from RG-PGC-1?-deficient mice leads to a strong induction of ?-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1? reduced ?-syn oligomerization and rescued ?-syn-mediated toxicity.Based on our results, we propose that PGC-1? downregulation and ?-syn oligomerization form a vicious circle, thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1? is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies.
SUBMITTER: Eschbach J
PROVIDER: S-EPMC4293280 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
ACCESS DATA