Research ArticleParkinson’s Disease

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

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Science Translational Medicine  07 Dec 2016:
Vol. 8, Issue 368, pp. 368ra174
DOI: 10.1126/scitranslmed.aag2210

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A mitochondrial target for slowing Parkinson's disease

Currently, there are no disease-modifying treatments to stall progression of Parkinson’s disease (PD). A drug in development to treat diabetes might provide a new way to slow the progression of PD according to new work by Ghosh and colleagues. The drug, MSDC-0160, targets a recently identified carrier of pyruvate (a major substrate for energy production) into the mitochondria. Ghosh et al. now show that this drug, which attenuates the mitochondrial pyruvate carrier, blocks neurodegeneration in several different cellular and animal models of PD. Furthermore, cellular autophagy was restored, and neuroinflammation was reduced in two mouse models of PD. These results support continued investigations into whether the mitochondrial pyruvate carrier will be a useful therapeutic target in PD.

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.

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