Alpha-synuclein-associated changes in PINK1-PRKN-mediated mitophagy are disease context dependent

Alpha-synuclein (alpha syn) aggregates are pathological features of several neurodegenerative conditions including Parkinson disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic-lysosomal system can contribute to the deposition of alpha syn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of alpha syn with the PINK1-PRKN-mediated mitochondrial autophagy pathway in cell models, alpha syn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) to mark them for degradation (mitophagy). We found that disease-causing multiplications of alpha syn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation-induced autophagy activation and by CRISPR/Cas9-mediated alpha syn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65-Ub response. We further confirmed increased pS65-Ub-immunopositive signals in mouse brain with alpha syn overexpression and in postmortem human disease brain. Of note, increased pS65-Ub was associated with neuronal Lewy body-type alpha syn pathology, but not glial cytoplasmic inclusions of alpha syn as seen in MSA. While our results add another layer of complexity to the crosstalk between alpha syn and the PINK1-PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65-Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease.