{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:02:29Z","timestamp":1787029349866,"version":"build-2736575974"},"reference-count":183,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington\u2019s disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell\u2019s ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca2+ homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine\u2019s mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine\u2019s S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD.<\/jats:p>","DOI":"10.3390\/ph18121900","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T13:42:52Z","timestamp":1765978972000},"page":"1900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pridopidine, a Potent and Selective Therapeutic Sigma-1 Receptor (S1R) Agonist for Treating Neurodegenerative Diseases"],"prefix":"10.3390","volume":"18","author":[{"given":"Noga","family":"Gershoni Emek","sequence":"first","affiliation":[{"name":"Prilenia Therapeutics, BV, 1411 DC Naarden, The Netherlands"}],"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, BV, 1411 DC Naarden, The Netherlands"},{"name":"Department of Neurology, School of Medicine, Yale University, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Geva","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics, BV, 1411 DC Naarden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Fekete","sequence":"additional","affiliation":[{"name":"SigmaDrugs Research, 1012 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9292-884X","authenticated-orcid":false,"given":"Carmen","family":"Abate","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2013Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5159-1419","authenticated-orcid":false,"given":"Michael R.","family":"Hayden","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics, BV, 1411 DC Naarden, The Netherlands"},{"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"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/17460441.2021.1838483","article-title":"Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders","volume":"16","author":"Maurice","year":"2021","journal-title":"Expert Opin. 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