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Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits

Wouter Peelaerts, Liza Bergkvist, Sonia George, Michaela Johnson, Lindsay Meyerdirk, Emily Ku, Jennifer A. Steiner, Zachary Madaj, Jiyan Ma, Katelyn Becker, K. Peter R. Nilsson, Jerry Colca, Patrik Brundin
doi: https://doi.org/10.1101/2020.10.01.322115
Wouter Peelaerts
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
2KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium
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Liza Bergkvist
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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Sonia George
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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Michaela Johnson
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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Lindsay Meyerdirk
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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Emily Ku
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Jennifer A. Steiner
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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Zachary Madaj
3Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
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Jiyan Ma
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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Katelyn Becker
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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K. Peter R. Nilsson
4Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
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Jerry Colca
5Metabolic Solutions Development Company, Kalamazoo, MI, USA
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Patrik Brundin
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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  • For correspondence: Patrik.Brundin@vai.org
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Abstract

Epidemiological studies suggest a link between type-2 diabetes and Parkinson’s disease (PD) risk. Treatment of type-2 diabetes with insulin sensitizing drugs lowers the risk of PD. We previously showed that the insulin sensitizing drug, MSDC-0160, ameliorates pathogenesis in some animal models of PD. MSDC-0160 reversibly binds the mitochondrial pyruvate carrier (MPC) protein complex, which has an anti-inflammatory effect and restores metabolic deficits. Since PD is characterized by the deposition of α-synuclein (αSyn), we hypothesized that inhibiting the MPC might directly inhibit αSyn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of αSyn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based αSyn overexpressing model and a pre-formed fibril (PFF) αSyn seeding model with MSDC-0160. These two models present with distinct types of αSyn pathology but lack inflammatory or autophagy deficits. Contrary to our hypothesis, we found that a modulation of MPC in these models did not reduce the accumulation αSyn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of the αSyn. These results are consistent with the lack of a direct effect on MPC modulation on synuclein clearance in these models.

Competing Interest Statement

P.B. receives commercial support as a consultant from Calico Life Sciences, CureSen, Idorsia Pharmaceuticals, Lundbeck A/S, AbbVie, Fujifilm-Cellular Dynamics International, and Axial Biotherapeutics. He has received commercial support for research from Lundbeck A/S and Roche. He has ownership interests in Acousort AB and Gilead. All other authors declare no additional competing financial interests.

Footnotes

  • ↵# Current affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 01, 2020.
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Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits
Wouter Peelaerts, Liza Bergkvist, Sonia George, Michaela Johnson, Lindsay Meyerdirk, Emily Ku, Jennifer A. Steiner, Zachary Madaj, Jiyan Ma, Katelyn Becker, K. Peter R. Nilsson, Jerry Colca, Patrik Brundin
bioRxiv 2020.10.01.322115; doi: https://doi.org/10.1101/2020.10.01.322115
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Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits
Wouter Peelaerts, Liza Bergkvist, Sonia George, Michaela Johnson, Lindsay Meyerdirk, Emily Ku, Jennifer A. Steiner, Zachary Madaj, Jiyan Ma, Katelyn Becker, K. Peter R. Nilsson, Jerry Colca, Patrik Brundin
bioRxiv 2020.10.01.322115; doi: https://doi.org/10.1101/2020.10.01.322115

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