{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:24:13Z","timestamp":1791404653136,"version":"4.3.3"},"reference-count":121,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T00:00:00Z","timestamp":1743292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["23K06367"],"award-info":[{"award-number":["23K06367"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores the potential convergent mechanisms underlying ALS pathogenesis, focusing on the roles of key proteins including NEK1, C21ORF2, cyclin F, VCP, and TDP-43. Recent studies suggest that mutations in C21ORF2 lead to the stabilization of NEK1, while cyclin F mutations activate VCP, resulting in TDP-43 aggregation. TDP-43 aggregation, a hallmark of ALS, impairs RNA processing and protein transport, both of which are essential for neuronal function. Furthermore, TDP-43 has emerged as a key player in DNA damage repair, translocating to DNA damage sites and recruiting repair proteins. Given that NEK1, VCP, and cyclin F are also involved in DNA repair, this review examines how these proteins may intersect to disrupt DNA damage repair mechanisms, contributing to ALS progression. Impaired DNA repair and protein homeostasis are suggested to be central downstream mechanisms in ALS pathogenesis. Ultimately, understanding the interplay between these pathways could offer novel insights into ALS and provide potential therapeutic targets. This review aims to highlight the emerging connections between protein aggregation, DNA damage repair, and cellular dysfunction in ALS, fostering a deeper understanding of its molecular basis and potential avenues for intervention.<\/jats:p>","DOI":"10.3390\/genes16040407","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:10:07Z","timestamp":1743397807000},"page":"407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Molecular Intersection of NEK1, C21ORF2, Cyclin F, and VCP in ALS Pathogenesis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3347-1628","authenticated-orcid":false,"given":"Yasuaki","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Neurology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"},{"name":"Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8872-6129","authenticated-orcid":false,"given":"Tadashi","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"},{"name":"Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0084, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Institute of Gene Research, Yamaguchi University Science Research Center, Ube 755-8505, Japan"},{"name":"Advanced Technology Institute, Life Science Division, Yamaguchi University, Yamaguchi 755-8611, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0134-6401","authenticated-orcid":false,"given":"Keiko","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"},{"name":"Research Infrastructure Management Center, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,30]]},"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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