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Peroxisome proliferator\u2010activated receptor \u03b3 coactivator 1\u03b1 (PGC\u20101\u03b1), 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\u20101\u03b1 in mitochondria, no studies have addressed whether PGC\u20101\u03b1 directly influences oligomerization of \u03b1\u2010syn or whether \u03b1\u2010syn oligomers impact PGC\u20101\u03b1 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>We tested whether pharmacological or genetic activation of PGC\u20101\u03b1 or PGC\u201011\u03b1 knockdown could modulate the oligomerization of \u03b1\u2010syn in vitro by using an \u03b1\u2010syn \u2010fragment complementation assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we found that both PGC\u20101\u03b1 reference gene (RG\u2010PGC\u20101\u03b1) and the central nervous system (CNS)\u2010specific PGC\u20101\u03b1 (CNS\u2010PGC\u20101\u03b1) are downregulated in human PD brain, in A30P \u03b1\u2010syn transgenic animals, and in a cell culture model for \u03b1\u2010syn oligomerization. Importantly, downregulation of both RG\u2010PGC\u20101\u03b1 and CNS\u2010PGC\u20101\u03b1 in cell culture or neurons from RG\u2010PGC\u20101\u03b1\u2013deficient mice leads to a strong induction of \u03b1\u2010syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG\u2010PGC\u20101\u03b1 reduced \u03b1\u2010syn oligomerization and rescued \u03b1\u2010syn\u2013mediated toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Based on our results, we propose that PGC\u20101\u03b1 downregulation and \u03b1\u2010syn oligomerization form a vicious circle, thereby influencing and\/or potentiating each other. Our data indicate that restoration of PGC\u20101\u03b1 is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies. 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