{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T19:54:55Z","timestamp":1785354895955,"version":"3.55.0"},"reference-count":71,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Prilenia Therapeutics B.V."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident protein enriched at the mitochondria-associated ER membranes (MAMs) that supports ER homeostasis, preserves mitochondrial function, and enhances cell survival under stress. Disruptions of MAM integrity and prolonged ER stress are well-recognized pathological features of amyotrophic lateral sclerosis (ALS), contributing to motor neuron dysfunction and degeneration. In this study, we evaluated the protective effects of pridopidine, a highly selective and potent S1R agonist currently in clinical development for Huntington\u2019s disease (HD) and ALS, using neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) from a patient with sporadic ALS. Exposure of ALS NPCs to the ER stressor tunicamycin increased the ER stress markers binding immunoglobulin protein (BiP) and C\/EBP homologous protein (CHOP), disrupted mitochondrial membrane potential, upregulated expression of the mitochondrial apoptotic marker, BAX, increased caspase-3 activation, and reduced cell viability. Pridopidine significantly attenuated tunicamycin-induced BiP and CHOP expression in a biphasic, dose-dependent manner (with maximal efficacy at 1 \u00b5M), consistent with the typical pharmacology of S1R agonists. Pridopidine restored mitochondrial membrane potential, reduced mitochondrial apoptotic signaling, shown by decreased BAX expression and caspase-3 activation, and improved survival of ALS-NPCs under ER stress. Co-treatment with the selective S1R antagonist, NE-100, attenuated these effects, supporting an S1R-mediated mechanism of action for pridopidine. Together, these results demonstrate that S1R activation by pridopidine mitigates ER-stress-induced mitochondrial dysfunction and cell loss in ALS-NPCs, resulting in enhanced survival of NPCs supporting the therapeutic potential of pridopidine in ALS.<\/jats:p>","DOI":"10.3390\/ijms27083489","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T10:29:08Z","timestamp":1776162548000},"page":"3489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pridopidine Protects ALS Patient-Derived Neural Progenitor Cells via Sigma-1 Receptor Activation"],"prefix":"10.3390","volume":"27","author":[{"given":"May","family":"Meltzer","sequence":"first","affiliation":[{"name":"Prilenia Therapeutics B.V., 1411 DC Naarden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4828-0811","authenticated-orcid":false,"given":"Maya Shefler","family":"Zamir","sequence":"additional","affiliation":[{"name":"Avram and Stella Goren-Goldstein Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Tzuri","sequence":"additional","affiliation":[{"name":"Avram and Stella Goren-Goldstein Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0099-8814","authenticated-orcid":false,"given":"Andrew M.","family":"Tan","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics B.V., 1411 DC Naarden, The Netherlands"},{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Geva","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics B.V., 1411 DC Naarden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Hayden","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics B.V., 1411 DC Naarden, The Netherlands"},{"name":"Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel"},{"name":"Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel G.","family":"Lichtenstein","sequence":"additional","affiliation":[{"name":"Avram and Stella Goren-Goldstein Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1111\/ene.14393","article-title":"Amyotrophic Lateral Sclerosis: A Clinical Review","volume":"27","author":"Masrori","year":"2020","journal-title":"Eur. J. 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