{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:32:24Z","timestamp":1783517544073,"version":"3.55.0"},"reference-count":60,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AriSLA","award":["NOSRESCUEALS"],"award-info":[{"award-number":["NOSRESCUEALS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The pathological loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to extensive alterations in RNA metabolism and a broad number of neuronal transcripts. However, the key effectors linking TDP-43 dysfunction to synaptic defects remain unclear. In this study, using Drosophila and human iPSC-derived motoneurons, we identify Rab4 as a direct and conserved target of TDP-43, whose expression is necessary and sufficient to recover synaptic vesicle recycling, neuromuscular junction growth, and locomotor function in TDP-43-deficient motoneurons. Moreover, Rab4 activity promotes the presynaptic recruitment of futsch\/MAP1B, a microtubule-associated protein also regulated by TDP-43, which autonomously supports synaptic growth and vesicle turnover. Together, these findings define a TDP-43\/Rab4\/futsch\/MAP1B regulatory axis that couples endosomal dynamics to cytoskeletal assembly. Furthermore, this functionally coherent module provides a mechanistic basis for understanding how synaptic vulnerability is amplified in disease and offers a framework to identify key compensatory targets capable of sustaining neuronal function in the absence of TDP-43.<\/jats:p>","DOI":"10.3390\/ijms262211030","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:49:43Z","timestamp":1763120983000},"page":"11030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and Human ALS Models"],"prefix":"10.3390","volume":"26","author":[{"given":"Monsurat","family":"Gbadamosi","sequence":"first","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0356-4947","authenticated-orcid":false,"given":"Giulia","family":"Romano","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Simbula","sequence":"additional","affiliation":[{"name":"Institute for Genetic and Biomedical Research, The National Research Council (CNR), 09042 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5010-7269","authenticated-orcid":false,"given":"Giulia","family":"Canarutto","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy"},{"name":"Department of Life Sciences, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5412-7785","authenticated-orcid":false,"given":"Linda","family":"Ottoboni","sequence":"additional","affiliation":[{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"},{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-969X","authenticated-orcid":false,"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"},{"name":"Neuromuscular and Rare Diseases Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8486-7546","authenticated-orcid":false,"given":"Fabian","family":"Feiguin","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,14]]},"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. 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