TY - JOUR T1 - Activation of AMPK/mTORC1-mediated autophagy by metformin reverses Clk1 deficiency - sensitized dopaminergic neuronal death JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.109512 SP - mol.117.109512 AU - Qiuting Yan AU - Chaojun Han AU - Guanghui Wang AU - John L. Waddington AU - Longtai Zheng AU - Xuechu Zhen Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/10/12/mol.117.109512.abstract N2 - The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson's disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for Coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explored the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrated that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in SNc of Clk+/- mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects. These mechanistic studies revealed that Clk1 regulated the AMPK/mTORC1 pathway, which in turn impaired the autophagy-lysosome pathway and TFEB nuclear translocation; this promoted dopaminergic neuronal damage in vivo and in vitro that ultimately contributed to sensitize MPTP-induced dopaminergic neuronal death and behavioral impairments in Clk1-deficient mice. Moreover, we report that activation of autophagy by the AMPK activator metformin increased dopaminergic neuronal survival in vitro and in the MPTP-induced PD model in Clk1 mutant mice. These results reveal that Clk1 plays a direct role in dopaminergic neuronal survival via regulating autophagy-lysosome pathways that may contribute to the pathological development of PD. Modulation of Clk1 activity may represent a potential therapeutic target for PD. ER -