{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T04:38:23Z","timestamp":1793248703456,"version":"4.5.0"},"reference-count":90,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["GR-2021-12375436"],"award-info":[{"award-number":["GR-2021-12375436"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AriSLA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mutations in the TANK-binding kinase 1 (TBK1) gene represent a significant genetic link across the Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) spectrum. As a multifunctional serine\/threonine kinase, TBK1 serves as a central orchestrator of the autophagy\u2013lysosome pathway, regulating critical stages from initial cargo recognition and autophagosome biogenesis to vesicle maturation and lysosomal fusion. This review examines the mechanisms by which TBK1 coordinates these diverse autophagic functions. We then focus on how ALS\/FTD-associated mutations\u2014ranging from truncating variants causing haploinsufficiency to domain-specific missense mutations\u2014disrupt these essential processes.<\/jats:p>","DOI":"10.3390\/cells15050477","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T09:22:14Z","timestamp":1772788934000},"page":"477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["TBK1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Mechanistic Insights into Impaired Autophagy and Proteostatic Failure"],"prefix":"10.3390","volume":"15","author":[{"given":"Francesca","family":"Manganelli","sequence":"first","affiliation":[{"name":"IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC), Via del Fosso di Fiorano 64, 00143 Rome, Italy"},{"name":"Graduate Program in Cell and Molecular Biology, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Perfetto","sequence":"additional","affiliation":[{"name":"IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC), Via del Fosso di Fiorano 64, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Carletta","sequence":"additional","affiliation":[{"name":"IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC), Via del Fosso di Fiorano 64, 00143 Rome, Italy"},{"name":"Graduate Program in Science and Biomedical Technologies, Department of Science, University \u201cRoma Tre\u201d, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7722-7284","authenticated-orcid":false,"given":"Valeria","family":"Gerbino","sequence":"additional","affiliation":[{"name":"IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC), Via del Fosso di Fiorano 64, 00143 Rome, Italy"},{"name":"Institute of Translational Pharmacology, National Research Council (CNR), 00133 Rome, Italy"},{"name":"Zuckerman Institute of Mind Brain and Behavior, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1056\/NEJMra1603471","article-title":"Amyotrophic Lateral Sclerosis","volume":"377","author":"Brown","year":"2017","journal-title":"N. 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