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This accumulation causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and devastating cognitive decline. While the etiology of these conditions remains largely unknown, microglia, the resident immune cells of the central nervous system (CNS), have been consistently implicated in the pathogenesis of synucleinopathies. Microglia are generally believed to be neuroprotective in the early stages of \u03b1-syn accumulation and contribute to further neurodegeneration in chronic disease states. While the molecular mechanisms by which microglia achieve this role are still being investigated, here we highlight the major findings to date. In this review, we describe how structural varieties of inherently disordered \u03b1-syn result in varied microglial receptor-mediated interactions. We also summarize which microglial receptors enable cellular recognition and uptake of \u03b1-syn. Lastly, we review the downstream effects of \u03b1-syn processing within microglia, including spread to other brain regions resulting in neuroinflammation and neurodegeneration in chronic disease states. Understanding the mechanism of microglial interactions with \u03b1-syn is vital to conceptualizing molecular targets for novel therapeutic interventions. In addition, given the significant diversity in the pathophysiology of synucleinopathies, such molecular interactions are vital in gauging all potential pathways of neurodegeneration in the disease state.<\/jats:p>","DOI":"10.3390\/ijms24032477","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:31:27Z","timestamp":1675053087000},"page":"2477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["The Interplay between \u03b1-Synuclein and Microglia in \u03b1-Synucleinopathies"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-7506","authenticated-orcid":false,"given":"Jacob S.","family":"Deyell","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"},{"name":"UCI Institute for Neurotherapeutics, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3272-7370","authenticated-orcid":false,"given":"Manjari","family":"Sriparna","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University School of Medicine, Richmond, VA 23223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6215-4959","authenticated-orcid":false,"given":"Mingyao","family":"Ying","sequence":"additional","affiliation":[{"name":"Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-556X","authenticated-orcid":false,"given":"Xiaobo","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA"},{"name":"Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13024-021-00501-z","article-title":"Neuropathology and Molecular Diagnosis of Synucleinopathies","volume":"16","author":"Koga","year":"2021","journal-title":"Mol. 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