Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson's disease
Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson's disease
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DOI：
10.1126/scitranslmed.aag2210
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发表时间：
2016-12-07
影响因子：
17.1
通讯作者：
Brundin, Patrik
中科院分区：
文献类型：
--
作者：
Ghosh, Anamitra;Tyson, Trevor;Brundin, Patrik
线粒体和自噬功能障碍以及神经炎症参与帕金森病（PD）的病理生理学。我们假设，靶向线粒体丙酮酸载体（MPC），影响mTOR（雷帕霉素的哺乳动物靶标）激活的细胞代谢的关键控制器，可能会减弱PD动物模型中黑质多巴胺能神经元的神经变性。为了测试这一点，我们使用了MSDC-0160，一种专门针对MPC的化合物，以降低其活性。MSDC-0160在鼠和培养的人中脑多巴胺神经元中以及在基于α-突触核蛋白的秀丽隐杆线虫模型中保护免受1-甲基-4-苯基吡啶鎓（MPP+）损伤。在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）治疗的小鼠中，MSDC-0160改善了运动行为，增加了黑质多巴胺能神经元的存活，提高了纹状体多巴胺水平，并减少了神经炎症。MPC的长期靶向保护运动功能，挽救黑质纹状体通路，并减少PD的缓慢进行性Engrailed 1（En 1（+/-））遗传小鼠模型中的神经炎症。在多种模型中靶向MPC导致线粒体功能和mTOR信号传导的调节，自噬正常化和胶质细胞活化减少。我们的工作表明，由靶向MPC引起的代谢信号的变化在几种PD模型中具有神经保护和抗炎作用，这表明MPC可能是PD中有用的治疗靶点。
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 neuro-degeneration 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.