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

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