Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration

Misfolded alpha-synuclein (Syn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson's disease (PD). The contribution of Syn to PD is well established, but the detailed mechanism remains obscure. Using a model in which Syn aggregation in primary neurons was seeded by exogenously added, preformed Syn amyloid fibrils (PFF), we found that a majority of pathogenic Syn (indicated by serine 129 phosphorylated Syn, ps-Syn) was membrane-bound and associated with mitochondria. In contrast, only a minuscule amount of physiological Syn was mitochondrial bound. In vitro, Syn PFF displayed a stronger binding to purified mitochondria than did Syn monomer, revealing a preferential mitochondria binding by aggregated Syn. This selective mitochondrial ps-Syn accumulation was confirmed in other neuronal and animal Syn aggregation models that do not require exogenously added PFF and, more importantly, in postmortem brain tissues of patients suffering from PD and other neurodegenerative diseases with Syn aggregation (-synucleinopathies). We also showed that the mitochondrial ps-Syn accumulation was accompanied by defects in cellular respiration in primary neurons, suggesting a link to mitochondrial dysfunction. Together, our results show that, contrary to physiological Syn, pathogenic Syn aggregates preferentially bind to mitochondria, indicating mitochondrial dysfunction as the common downstream mechanism for -synucleinopathies. Our findings suggest a plausible model explaining the formation and the peculiar morphology of Lewy body and reveal that disrupting the interaction between ps-Syn and the mitochondria is a therapeutic target for -synucleinopathies.