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Here, we used arrayed CRISPR\u2010mediated gene activation and ablation to discover new pSyn\n                    <jats:sup>129<\/jats:sup>\n                    modulators. Using quadruple\u2010guide RNAs (qgRNAs) and Cas9, or an inactive Cas9 fused to a synthetic transactivator, we ablated 2304 and activated 2428 human genes related to mitochondria, trafficking, and motility functions in HEK293 cells. After exposure of cells to \u03b1Syn fibrils, pSyn\n                    <jats:sup>129<\/jats:sup>\n                    signals were recorded by high\u2010throughput fluorescence microscopy and aggregates were identified by image analysis. We found that pSyn\n                    <jats:sup>129<\/jats:sup>\n                    was increased by activating the mitochondrial protein\n                    <jats:italic>OXR1,<\/jats:italic>\n                    which decreased ATP levels and altered the mitochondrial membrane potential. Instead, pSyn\n                    <jats:sup>129<\/jats:sup>\n                    was reduced by ablation of the endoplasmic reticulum (ER)\u2010associated protein\n                    <jats:italic>EMC4<\/jats:italic>\n                    , which enhanced ER\u2010driven autophagic flux and lysosomal clearance. OXR1 activation preferentially modulated cellular reactions to fibrils derived from multiple system atrophy (MSA) patients, whereas EMC4 ablation broadly reduced pSyn\n                    <jats:sup>129<\/jats:sup>\n                    across diverse \u03b1Syn polymorphs. These findings were confirmed in human iPSC\u2010derived cortical and dopaminergic neurons, where OXR1 preferentially promoted somatic aggregation and EMC4 reduced both somatic and neuritic aggregates. These results uncover previously unrecognized roles for OXR1 and EMC4 in \u03b1Syn aggregation, thereby broadening our mechanistic understanding of synucleinopathies.\n                  <\/jats:p>","DOI":"10.1002\/2211-5463.70233","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T17:41:15Z","timestamp":1774892475000},"page":"1563-1592","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Large\u2010scale bidirectional arrayed genetic screens identify\n                    <scp>\n                      <i>OXR1<\/i>\n                    <\/scp>\n                    and\n                    <scp>\n                      <i>EMC4<\/i>\n                    <\/scp>\n                    as modifiers of\n                    <scp>\u03b1Synuclein<\/scp>\n                    aggregation"],"prefix":"10.1002","volume":"16","author":[{"given":"Sandesh","family":"Neupane","sequence":"first","affiliation":[{"name":"Institute for the Science of the Aging Brain  St. Gallen Switzerland"},{"name":"Institute of Neuropathology University of Zurich  Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8792-7199","authenticated-orcid":false,"given":"Lea","family":"Nikoli\u0107","sequence":"additional","affiliation":[{"name":"Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA)  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Maraio","sequence":"additional","affiliation":[{"name":"Institute for the Science of the Aging Brain  St. Gallen Switzerland"},{"name":"Institute of Neuropathology University of Zurich  Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Goiran","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute\u2010Hospital McGill University  Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Karpilovsky","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute\u2010Hospital McGill University  Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2579-6271","authenticated-orcid":false,"given":"Stefano","family":"Sellitto","sequence":"additional","affiliation":[{"name":"Department of Biology University of Padova  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vangelis","family":"Bouris","sequence":"additional","affiliation":[{"name":"Institute for the Science of the Aging Brain  St. Gallen Switzerland"},{"name":"Institute of Neuropathology University of Zurich  Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang\u2010An","family":"Yin","sequence":"additional","affiliation":[{"name":"Aging and Regeneration Center, School of Basic Medical Sciences Tsinghua University  Beijing P. 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