Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization

Judith Eschbach, Björn Von Einem, Kathrin Müller, Hanna Bayer, Annika Scheffold, Bradley E. Morrison, K. Lenhard Rudolph, Dietmar R. Thal, Anke Witting, Patrick Weydt, Markus Otto, Michael Fauler, Birgit Liss, Pamela J McLean, Albert R. La Spada, Albert C. Ludolph, Jochen H. Weishaupt, Karin M. Danzer

Research output: Contribution to journalArticle

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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. Materials and 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. Interpretation: 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.

Original languageEnglish (US)
Pages (from-to)15-32
Number of pages18
JournalAnnals of Neurology
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2015

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Synucleins
Peroxisome Proliferator-Activated Receptors
Parkinson Disease
Down-Regulation
Central Nervous System
Cell Culture Techniques
Pharmacology
Genetically Modified Animals
Organelle Biogenesis
Energy Metabolism
Mitochondria
Neurons
Brain
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Eschbach, J., Von Einem, B., Müller, K., Bayer, H., Scheffold, A., Morrison, B. E., ... Danzer, K. M. (2015). Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization. Annals of Neurology, 77(1), 15-32. https://doi.org/10.1002/ana.24294

Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization. / Eschbach, Judith; Von Einem, Björn; Müller, Kathrin; Bayer, Hanna; Scheffold, Annika; Morrison, Bradley E.; Rudolph, K. Lenhard; Thal, Dietmar R.; Witting, Anke; Weydt, Patrick; Otto, Markus; Fauler, Michael; Liss, Birgit; McLean, Pamela J; La Spada, Albert R.; Ludolph, Albert C.; Weishaupt, Jochen H.; Danzer, Karin M.

In: Annals of Neurology, Vol. 77, No. 1, 01.01.2015, p. 15-32.

Research output: Contribution to journalArticle

Eschbach, J, Von Einem, B, Müller, K, Bayer, H, Scheffold, A, Morrison, BE, Rudolph, KL, Thal, DR, Witting, A, Weydt, P, Otto, M, Fauler, M, Liss, B, McLean, PJ, La Spada, AR, Ludolph, AC, Weishaupt, JH & Danzer, KM 2015, 'Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization', Annals of Neurology, vol. 77, no. 1, pp. 15-32. https://doi.org/10.1002/ana.24294
Eschbach, Judith ; Von Einem, Björn ; Müller, Kathrin ; Bayer, Hanna ; Scheffold, Annika ; Morrison, Bradley E. ; Rudolph, K. Lenhard ; Thal, Dietmar R. ; Witting, Anke ; Weydt, Patrick ; Otto, Markus ; Fauler, Michael ; Liss, Birgit ; McLean, Pamela J ; La Spada, Albert R. ; Ludolph, Albert C. ; Weishaupt, Jochen H. ; Danzer, Karin M. / Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization. In: Annals of Neurology. 2015 ; Vol. 77, No. 1. pp. 15-32.
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AU - Von Einem, Björn

AU - Müller, Kathrin

AU - Bayer, Hanna

AU - Scheffold, Annika

AU - Morrison, Bradley E.

AU - Rudolph, K. Lenhard

AU - Thal, Dietmar R.

AU - Witting, Anke

AU - Weydt, Patrick

AU - Otto, Markus

AU - Fauler, Michael

AU - Liss, Birgit

AU - McLean, Pamela J

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N2 - 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. Materials and 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. Interpretation: 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.

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