{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:36:39Z","timestamp":1772930199938,"version":"3.50.1"},"reference-count":68,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MUR","award":["PRIN2022 N. 2022XTM2S3"],"award-info":[{"award-number":["PRIN2022 N. 2022XTM2S3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is currently no cure. Dominant mutations in the TARDBP gene are causative of ALS. In particular, the p. G376D substitution in TDP-43 causes familial ALS and it is associated with TDP-43 mislocalization in the cytosol, increased presence of cytoplasmic aggregates, and lysosomal and mitochondrial dysfunction. We previously designed a small interfering RNA (siRNA) that specifically targets and silences the mutant allele and we demonstrated that, in patient-derived fibroblasts, it can reduce TDP-43 aggregation, decrease oxidative stress, and improve cell viability. Here, we investigated the ability of this siRNA to revert some ALS-associated pathological phenotypes in motor neurons derived from induced pluripotent stem cells (iPSCs), as motor neurons are the primary cells affected in ALS. siRNA treatment reduced TDP-43 mislocalization, enhanced lysosomal function and cell viability, and decreased oxidative stress. These findings indicate that this allele-specific siRNA effectively reverses key ALS-related cellular deficits in motor neurons, representing a promising candidate for targeted therapy in patients carrying the TDP-43 G376D mutation.<\/jats:p>","DOI":"10.3390\/biom16030393","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T11:52:11Z","timestamp":1772711531000},"page":"393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective Silencing of TDP-43 P. G376D Mutation Reverses Key Amyotrophic Lateral Sclerosis-Related Cellular Deficits"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4987-3561","authenticated-orcid":false,"given":"Roberta","family":"Romano","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-6868","authenticated-orcid":false,"given":"Giorgia","family":"Ruotolo","sequence":"additional","affiliation":[{"name":"Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"},{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Perrone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Tomaselli","sequence":"additional","affiliation":[{"name":"Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Mazzoni","sequence":"additional","affiliation":[{"name":"Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella","family":"Spataro","sequence":"additional","affiliation":[{"name":"Intensive Neurorehabilitation Unit, Villa delle Ginestre Hospital, 90135 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-1783","authenticated-orcid":false,"given":"Francesca Luisa","family":"Conforti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Rosati","sequence":"additional","affiliation":[{"name":"Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"},{"name":"Departmental Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-6183","authenticated-orcid":false,"given":"Cecilia","family":"Bucci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.jgg.2025.05.008","article-title":"Genetic architecture of amyotrophic lateral sclerosis: A comprehensive review","volume":"52","author":"Yuan","year":"2025","journal-title":"J. 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