Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson's Disease Pathology

Aberrant secretion and accumulation of alpha-synuclein (alpha-Syn) as well as the loss of parkin function are associated with the pathogenesis of Parkinson's disease (PD). Our previous study suggested a functional interaction between those two proteins, showing that the extracellular alpha-Syn evoked post-translational modifications of parkin, leading to its autoubiquitination and degradation. While parkin plays an important role in mitochondrial biogenesis and turnover, including mitochondrial fission/fusion as well as mitophagy, the involvement of parkin deregulation in alpha-Syn-induced mitochondrial damage is largely unknown. In the present study, we demonstrated that treatment with exogenous alpha-Syn triggers mitochondrial dysfunction, reflected by the depolarization of the mitochondrial membrane, elevated synthesis of the mitochondrial superoxide anion, and a decrease in cellular ATP level. At the same time, we observed a protective effect of parkin overexpression on alpha-Syn-induced mitochondrial dysfunction. alpha-Syn-dependent disturbances of mitophagy were also shown to be directly related to reduced parkin levels in mitochondria and decreased ubiquitination of mitochondrial proteins. Also, alpha-Syn impaired mitochondrial biosynthesis due to the parkin-dependent reduction of PGC-1 alpha protein levels. Finally, loss of parkin function as a result of alpha-Syn treatment induced an overall breakdown of mitochondrial homeostasis that led to the accumulation of abnormal mitochondria. These findings may thus provide the first compelling evidence for the direct association of alpha-Syn-mediated parkin depletion to impaired mitochondrial function in PD. We suggest that improvement of parkin function may serve as a novel therapeutic strategy to prevent mitochondrial impairment and neurodegeneration in PD (thereby slowing the progression of the disease).