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Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic\u2010lysosomal system can contribute to the deposition of \u03b1syn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of \u03b1syn with the PINK1\u2010PRKN\u2010mediated mitochondrial autophagy pathway in cell models, \u03b1syn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65\u2010Ub) to mark them for degradation (mitophagy). We found that disease\u2010causing multiplications of \u03b1syn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation\u2010induced autophagy activation and by CRISPR\/Cas9\u2010mediated \u03b1syn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65\u2010Ub response. We further confirmed increased pS65\u2010Ub\u2010immunopositive signals in mouse brain with \u03b1syn overexpression and in postmortem human disease brain. Of note, increased pS65\u2010Ub was associated with neuronal Lewy body\u2010type \u03b1syn pathology, but not glial cytoplasmic inclusions of \u03b1syn as seen in MSA. While our results add another layer of complexity to the crosstalk between \u03b1syn and the PINK1\u2010PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65\u2010Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease.<\/jats:p>","DOI":"10.1111\/bpa.13175","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T01:50:32Z","timestamp":1685584232000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Alpha\u2010synuclein\u2010associated changes in PINK1\u2010PRKN\u2010mediated mitophagy are disease context dependent"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3011-4378","authenticated-orcid":false,"given":"Xu","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor 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