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

Peelaerts, W.; Bergkvist, L.; George, S.; Johnson, M. E.; Meyerdirk, l.; Kuhn, E.; Steiner, J.; Madaj, Z.; Ma, J.; Becker, K.; Nilsson, P. R.; Colca, J.; Brundin, P.

doi:10.1101/2020.10.01.322115

bioRxiv · 10.1101/2020.10.01.322115

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

Peelaerts, W.·Bergkvist, L.·George, S.·Johnson, M. E.·Meyerdirk, l.·Kuhn, E.·Steiner, J.·Madaj, Z.·Ma, J.·Becker, K.·Nilsson, P. R.·Colca, J.·Brundin, P.

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Abstract

Epidemiological studies suggest a link between type-2 diabetes and Parkinsons 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 -synuclein (Syn), we hypothesized that inhibiting the MPC might directly inhibit Syn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of Syn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based Syn overexpressing model and a pre-formed fibril (PFF) Syn seeding model with MSDC-0160. These two models present with distinct types of Syn 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 Syn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of the Syn. These results are consistent with the lack of a direct effect on MPC modulation on synuclein clearance in these models.

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Peelaerts, W., Bergkvist, L., George, S., Johnson, M. E., Meyerdirk, l., Kuhn, E., Steiner, J., Madaj, Z., Ma, J., Becker, K., Nilsson, P. R., Colca, J., Brundin, P.. 2020-10-01. Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits. https://doi.org/10.1101/2020.10.01.322115

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