{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T19:48:58Z","timestamp":1791575338193,"version":"4.3.4"},"reference-count":93,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T00:00:00Z","timestamp":1618272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["20K22663, 18K15471"],"award-info":[{"award-number":["20K22663, 18K15471"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A common pathological hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis, is cytoplasmic mislocalization and aggregation of nuclear RNA-binding protein TDP-43. Perry disease, which displays inherited atypical parkinsonism, is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit of the dynactin complex. Dynactin associates with the microtubule-based motor cytoplasmic dynein and is required for dynein-mediated long-distance retrograde transport. Perry disease-linked missense mutations (e.g., p.G71A) reside within the CAP-Gly domain and impair the microtubule-binding abilities of DCTN1. However, molecular mechanisms by which such DCTN1 mutations cause TDP-43 proteinopathy remain unclear. We found that DCTN1 bound to TDP-43. Biochemical analysis using a panel of truncated mutants revealed that the DCTN1 CAP-Gly-basic supradomain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. Remarkably, the p.G71A mutation affected the TDP-43-interacting ability of DCTN1. Overexpression of DCTN1G71A, the dynactin-domain fragment, or C-terminal fragment, but not the CAP-Gly-basic fragment, induced cytoplasmic mislocalization and aggregation of TDP-43, suggesting functional modularity among TDP-43-interacting domains of DCTN1. We thus identified DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43, thus providing insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies.<\/jats:p>","DOI":"10.3390\/ijms22083985","type":"journal-article","created":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T05:31:37Z","timestamp":1618291897000},"page":"3985","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation"],"prefix":"10.3390","volume":"22","author":[{"given":"Manami","family":"Deshimaru","sequence":"first","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"},{"name":"Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Kinoshita-Kawada","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0131-8646","authenticated-orcid":false,"given":"Takuya","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyoshi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saito","family":"Hirano","sequence":"additional","affiliation":[{"name":"National Hospital Organization, Kokura Medical Center, Kitakyushu, Fukuoka 802-8533, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiyoshi","family":"Ishidate","sequence":"additional","affiliation":[{"name":"Bioanalysis Unit, iCeMS Analysis Center, Institute for Integrated Cell-Material Sciences, Kyoto University Institute for Advanced Study, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Hiramoto","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6075-7329","authenticated-orcid":false,"given":"Yoshinari","family":"Uehara","sequence":"additional","affiliation":[{"name":"Faculty of Sports and Health Science, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7482-5935","authenticated-orcid":false,"given":"Hideyuki","family":"Okano","sequence":"additional","affiliation":[{"name":"Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Hirose","sequence":"additional","affiliation":[{"name":"Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Fujioka","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsunori","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1382-3159","authenticated-orcid":false,"given":"Junichi","family":"Yuasa-Kawada","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayasu","family":"Mishima","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-0981","authenticated-orcid":false,"given":"Yoshio","family":"Tsuboi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1146\/annurev.cellbio.20.012103.094623","article-title":"Dynactin","volume":"20","author":"Schroer","year":"2004","journal-title":"Annu. 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