Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson's disease

Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N. Hildebrandt, Jennifer A. Steiner, Zachary Madaj, Emily Schulz, Emily MacHiela, William G. McDonald, Martha L.Escobar Galvis, Jeffrey H. Kordower, Jeremy M. Van Raamsdonk, Jerry R. Colca, Patrik Brundin

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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 a-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.

Original languageEnglish (US)
Article number368ra174
JournalScience Translational Medicine
Volume8
Issue number368
DOIs
StatePublished - Dec 7 2016
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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