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Moreover, trans\u2010synaptic spread of \u03b1\u2010synuclein oligomers is hypothesized to mediate disease progression. Therapeutic approaches that effectively block \u03b1\u2010synuclein oligomer\u2010induced pathogenesis are urgently needed. Here, we show for the first time that \u03b1\u2010synuclein species isolated from human PD patient brain and recombinant \u03b1\u2010synuclein oligomers caused similar deficits in lipid vesicle trafficking rates in cultured rat neurons and glia, while \u03b1\u2010synuclein species isolated from non\u2010PD human control brain samples did not. Recombinant \u03b1\u2010synuclein oligomers also increased neuronal expression of lysosomal\u2010associated membrane protein\u20102A (LAMP\u20102A), the lysosomal receptor that has a critical role in chaperone\u2010mediated autophagy. Unbiased screening of several small molecule libraries (including the NIH Clinical Collection) identified sigma\u20102 receptor antagonists as the most effective at blocking \u03b1\u2010synuclein oligomer\u2010induced trafficking deficits and LAMP\u20102A upregulation in a dose\u2010dependent manner. These results indicate that antagonists of the sigma\u20102 receptor complex may alleviate \u03b1\u2010synuclein oligomer\u2010induced neurotoxicity and are a novel therapeutic approach for disease modification in PD and related \u03b1\u2010synucleinopathies.<\/jats:p>","DOI":"10.1002\/jnr.24782","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T18:11:27Z","timestamp":1611339087000},"page":"1161-1176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Sigma\u20102 receptor antagonists rescue neuronal dysfunction induced by Parkinson\u2019s patient brain\u2010derived \u03b1\u2010synuclein"],"prefix":"10.1002","volume":"99","author":[{"given":"Colleen S.","family":"Limegrover","sequence":"first","affiliation":[{"name":"Cognition Therapeutics Inc. 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