Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits
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...
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doaj-1a77645d12c548a3ba5d9c06a4db6d522021-02-17T10:29:42ZengUniversity of Münster / Open Journals SystemFree Neuropathology2699-44452020-11-011333310.17879/freeneuropathology-2020-30493049Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficitsWouter Peelaerts0Liza Bergkvist1Sonia George2Michaela Johnson3Lindsay Meyerdirk4Emily Schulz5Jennifer A. Steiner6Zachary Madaj7Jiyan Ma8Katelyn Becker9K. Peter R. Nilsson10Jerry R. Colca11Patrik Brundin12KU Leuven, Laboratory for Neurobiology and Gene Therapy, Dept. of Neurosciences, Leuven, Belgium; Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USABioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USADepartment of Physics, Chemistry and Biology, Linköping University, Linköping, SwedenMetabolic Solutions Development Company, Kalamazoo, MI, USACenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USAEpidemiological 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 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 of αSyn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of αSyn. These results are consistent with the lack of a direct effect of MPC modulation on synuclein clearance in these models.https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/3049parkinson's diseasesynucleinneurodegenerationmetabolismsynucleinopathy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wouter Peelaerts Liza Bergkvist Sonia George Michaela Johnson Lindsay Meyerdirk Emily Schulz Jennifer A. Steiner Zachary Madaj Jiyan Ma Katelyn Becker K. Peter R. Nilsson Jerry R. Colca Patrik Brundin |
spellingShingle |
Wouter Peelaerts Liza Bergkvist Sonia George Michaela Johnson Lindsay Meyerdirk Emily Schulz Jennifer A. Steiner Zachary Madaj Jiyan Ma Katelyn Becker K. Peter R. Nilsson Jerry R. Colca Patrik Brundin Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits Free Neuropathology parkinson's disease synuclein neurodegeneration metabolism synucleinopathy |
author_facet |
Wouter Peelaerts Liza Bergkvist Sonia George Michaela Johnson Lindsay Meyerdirk Emily Schulz Jennifer A. Steiner Zachary Madaj Jiyan Ma Katelyn Becker K. Peter R. Nilsson Jerry R. Colca Patrik Brundin |
author_sort |
Wouter Peelaerts |
title |
Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits |
title_short |
Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits |
title_full |
Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits |
title_fullStr |
Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits |
title_full_unstemmed |
Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits |
title_sort |
inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits |
publisher |
University of Münster / Open Journals System |
series |
Free Neuropathology |
issn |
2699-4445 |
publishDate |
2020-11-01 |
description |
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 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 of αSyn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of αSyn. These results are consistent with the lack of a direct effect of MPC modulation on synuclein clearance in these models. |
topic |
parkinson's disease synuclein neurodegeneration metabolism synucleinopathy |
url |
https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/3049 |
work_keys_str_mv |
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