Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity

Both alpha-Synuclein (alpha Syn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease (PD). Although studies suggest that alpha Syn and its missense mutant, A53T, preferentially accumulate in the mitochondria, the mechanisms by which alpha Syn and mitochondrial proteins regulate each other to trigger mitochondrial and neuronal toxicity are poorly understood. ATP-dependent Clp protease (ClpP), a mitochondrial matrix protease, plays an important role in regulating mitochondrial protein turnover and bioenergetics activity. Here, we show that the protein level of ClpP is selectively decreased in alpha Syn-expressing cell culture and neurons derived from iPS cells of PD patient carrying Syn A53T mutant, and in dopaminergic (DA) neurons of alpha Syn A53T mice and PD patient postmortem brains. Deficiency in ClpP induces an overload of mitochondrial misfolded/unfolded proteins, suppresses mitochondrial respiratory activity, increases mitochondrial oxidative damage and causes cell death. Overexpression of ClpP reduces alpha Syn-induced mitochondrial oxidative stress through enhancing the level of Superoxide Dismutase-2 (SOD2), and suppresses the accumulation of alpha Syn S129 phosphorylation and promotes neuronal morphology in neurons derived from PD patient iPS cells carrying alpha Syn A53T mutant. Moreover, we find that alpha Syn WT and A53T mutant interact with ClpP and suppress its peptidase activity. The binding of alpha Syn to ClpP further promotes a distribution of ClpP from soluble to insoluble cellular fraction in vitro and in vivo, leading to reduced solubility of ClpP. Compensating for the loss of ClpP in the substantia nigra of alpha Syn A53T mice by viral expression of ClpP suppresses mitochondrial oxidative damage, and reduces alpha Syn pathology and behavioral deficits of mice. Our findings provide novel insights into the mechanism underlying alpha Syn-induced neuronal pathology, and they suggest that ClpP might be a useful therapeutic target for PD and other synucleinopathies.