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Recent clinical trials in HD patients and preclinical studies in cellular and mouse HD models suggest a therapeutic potential for the high\u2010affinity S1R agonist pridopidine. However, the molecular mechanisms of the cytoprotective effect are unclear. We have previously reported strong induction of ER stress by toxic mutant huntingtin (mHtt) oligomers, which is reduced upon sequestration of these mHtt oligomers into large aggregates. Here, we show that pridopidine significantly ameliorates mHtt\u2010induced ER stress in cellular HD models, starting at low nanomolar concentrations. Pridopidine reduced the levels of markers of the three branches of the unfolded protein response (UPR), showing the strongest effects on the PKR\u2010like endoplasmic reticulum kinase (PERK) branch. The effect is S1R\u2010dependent, as it is abolished in cells expressing mHtt in which the S1R was deleted using CRISPR\/Cas9 technology. mHtt increased the level of the detergent\u2010insoluble fraction of S1R, suggesting a compensatory cellular mechanism that responds to increased ER stress. Pridopidine further enhanced the levels of insoluble S1R, suggesting the stabilization of activated S1R oligomers. These S1R oligomeric species appeared in ER\u2010localized patches, and not in the mitochondria\u2010associated membranes nor the ER\u2010derived quality control compartment. The colocalization of S1R with the chaperone BiP was significantly reduced by mHtt, and pridopidine restored this colocalization to normal, unstressed levels. Pridopidine increased toxic oligomeric mHtt recruitment into less toxic large sodium dodecyl sulfate\u2010insoluble aggregates, suggesting that this in turn reduces ER stress and cytotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15366-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15366","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T12:57:53Z","timestamp":1618837073000},"page":"467-481","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Pridopidine reduces mutant huntingtin\u2010induced endoplasmic reticulum stress by modulation of the Sigma\u20101 receptor"],"prefix":"10.1111","volume":"158","author":[{"given":"Marina","family":"Shenkman","sequence":"first","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research Cell Biology Division George Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel"},{"name":"Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Geva","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics Development LTD Herzliya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noga","family":"Gershoni\u2010Emek","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics Development LTD Herzliya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Hayden","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics Development LTD Herzliya 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