title: Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson's disease.
abstract: Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson's disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity. MSDC-0160 protected against 1-methyl-4-phenylpyridinium (MPP+) insult in murine and cultured human midbrain dopamine neurons and in an α-synuclein-based Caenorhabditis elegans model. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, MSDC-0160 improved locomotor behavior, increased survival of nigral dopaminergic neurons, boosted striatal dopamine levels, and reduced neuroinflammation. Long-term targeting of MPC preserved motor function, rescued the nigrostriatal pathway, and reduced neuroinflammation in the slowly progressive Engrailed1 (En1+/-) genetic mouse model of PD. Targeting MPC in multiple models resulted in modulation of mitochondrial function and mTOR signaling, with normalization of autophagy and a reduction in glial cell activation. Our work demonstrates that changes in metabolic signaling resulting from targeting MPC were neuroprotective and anti-inflammatory in several PD models, suggesting that MPC may be a useful therapeutic target in PD.
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Tyson
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: George
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Hildebrandt
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Steiner
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Madaj
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Schulz
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Machiela
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: McDonald
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Escobar Galvis
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.|Center for Brain Repair, Department of Pathology, Rush Medical College, Chicago, IL 60612, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Van Raamsdonk
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Colca
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA. patrik.brundin@vai.org.
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000737:chemistry; D000818:Animals; D001343:Autophagy; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D004298:Dopamine / Q000737:chemistry; D059290:Dopaminergic Neurons / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000276:immunology* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010101:Oxygen Consumption; D010300:Parkinson Disease / Q000276:immunology* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry; D019289:Pyruvic Acid / Q000737:chemistry*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry
chemical_list: C581095:MSDC-0160; D011725:Pyridines; D045162:Thiazolidinediones; D051844:alpha-Synuclein; D019289:Pyruvic Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine