title: Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization.
abstract: OBJECTIVE
  Aggregation of α-synuclein (α-syn) and α-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 γ coactivator 1α (PGC-1α), 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-1α in mitochondria, no studies have addressed whether PGC-1α directly influences oligomerization of α-syn or whether α-syn oligomers impact PGC-1α expression.
  
  
  METHODS
  We tested whether pharmacological or genetic activation of PGC-1α or PGC-11α knockdown could modulate the oligomerization of α-syn in vitro by using an α-syn -fragment complementation assay.
  
  
  RESULTS
  In this study, we found that both PGC-1α reference gene (RG-PGC-1α) and the central nervous system (CNS)-specific PGC-1α (CNS-PGC-1α) are downregulated in human PD brain, in A30P α-syn transgenic animals, and in a cell culture model for α-syn oligomerization. Importantly, downregulation of both RG-PGC-1α and CNS-PGC-1α in cell culture or neurons from RG-PGC-1α-deficient mice leads to a strong induction of α-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1α reduced α-syn oligomerization and rescued α-syn-mediated toxicity.
  
  
  CONCLUSIONS
  Based on our results, we propose that PGC-1α downregulation and α-syn oligomerization form a vicious circle, thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1α is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies.
authors.affiliation: Department of Neurology, Ulm University, Ulm, Germany; Inoviem Scientific, Strasbourg, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Eschbach
authors.forename: Björn
authors.initials: B
authors.lastname: von Einem
authors.forename: Kathrin
authors.initials: K
authors.lastname: Müller
authors.forename: Hanna
authors.initials: H
authors.lastname: Bayer
authors.forename: Annika
authors.initials: A
authors.lastname: Scheffold
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Morrison
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
authors.forename: Michael
authors.initials: M
authors.lastname: Fauler
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
authors.forename: Albert R La
authors.initials: AR
authors.lastname: Spada
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005910:Glioma / Q000473:pathology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013378:Substantia Nigra / Q000378:metabolism*; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D035181:TATA-Box Binding Protein; D014157:Transcription Factors; D051844:alpha-Synuclein; C040929:bafilomycin A1; D012319:RNA Polymerase II; D000077185:Resveratrol