TY - JOUR
T1 - Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson's disease
AU - Ghosh, Anamitra
AU - Tyson, Trevor
AU - George, Sonia
AU - Hildebrandt, Erin N.
AU - Steiner, Jennifer A.
AU - Madaj, Zachary
AU - Schulz, Emily
AU - MacHiela, Emily
AU - McDonald, William G.
AU - Galvis, Martha L.Escobar
AU - Kordower, Jeffrey H.
AU - Van Raamsdonk, Jeremy M.
AU - Colca, Jerry R.
AU - Brundin, Patrik
N1 - Funding Information:
The work presented here was supported by Cure Parkinson's Trust (to P.B.), Campbell Foundation (to P.B.), Spica Foundation (to P.B.), and Van Andel Research Institute (to P.B. and J.M.V.R.).
Publisher Copyright:
© 2016 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2016/12/7
Y1 - 2016/12/7
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aag2210
DO - 10.1126/scitranslmed.aag2210
M3 - Article
C2 - 27928028
AN - SCOPUS:85003601650
SN - 1946-6234
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 368
M1 - 368ra174
ER -