Mutual Exacerbation of Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Deregulation and α-Synuclein Oligomerization

ObjectiveAggregation 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. Materials and MethodsWe 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. ResultsIn 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. InterpretationBased 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. ANN NEUROL 2015;77:15-32