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

ABSTRACT: Both ?-Synuclein (?Syn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease (PD). Although studies suggest that ?Syn and its missense mutant, A53T, preferentially accumulate in the mitochondria, the mechanisms by which ?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 ?Syn-expressing cell culture and neurons derived from iPS cells of PD patient carrying ?Syn A53T mutant, and in dopaminergic (DA) neurons of ?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 ?Syn-induced mitochondrial oxidative stress through enhancing the level of Superoxide Dismutase-2 (SOD2), and suppresses the accumulation of ?Syn S129 phosphorylation and promotes neuronal morphology in neurons derived from PD patient iPS cells carrying ?Syn A53T mutant. Moreover, we find that ?Syn WT and A53T mutant interact with ClpP and suppress its peptidase activity. The binding of ?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 ?Syn A53T mice by viral expression of ClpP suppresses mitochondrial oxidative damage, and reduces ?Syn pathology and behavioral deficits of mice. Our findings provide novel insights into the mechanism underlying ?Syn-induced neuronal pathology, and they suggest that ClpP might be a useful therapeutic target for PD and other synucleinopathies.

PROVIDER: S-EPMC6531426 | BioStudies |

REPOSITORIES: biostudies

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