Clk1 Deficiency Inhibits Autophagy Through AMPK/mTORC1 Pathway That Sensitizes Dopaminergic Neuronal Death

Parkinson’s disease（PD）is one of most common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta（SNc）and the presence of Lewy bodies.Clk1（coq7）,a mitochondrial hydroxylase that is essential for Coenzyme Q（ubiquinone）biosynthesis.Here,we investigate the functional role of Clk1 in the regulation of dopaminergic neurons survival.We found that loss of Clk1 strongly increased MPTP neurotoxicity and inhibited autophagy.In contrast,overexpression of Clk1 significantly increased autophagy.Mechanistic studies demonstrated that Clk1 regulated TFEB nuclear translocation through AMPK/mTORC1signaling pathway.Importantly,activation of autopahgy by metformin（AMPK agonist）treatment protected dopaminergic neurons in Clk1-deficient PD models.Moreover,Clk1^+/-mutant mice showed inhibited the level of autophagy and signaling pathway in the striatum and substantia nigra（SNc）tissues.In MPTP-induced PD model,Clk^+/-mice showed more the loss of dopaminergic neurons and behavioral impairments compared with wild-type.However,pretreatment with metformin significantly relived Clk1-linked neurotoxicity.Taken together,our data indicated that regulation of AMPK/mTORC1/TFEB pathway and influenced autophagy may contribute to Clk1-linked neurotoxicity.