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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["ASAP-000350"],"award-info":[{"award-number":["ASAP-000350"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["ASAP-000350"],"award-info":[{"award-number":["ASAP-000350"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,6,15]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Missense mutations in TANK-binding kinase 1 (TBK1) have diverse biophysical and biochemical effects on the molecule and are associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. TBK1 plays an essential role in clearing damaged mitochondria. Here, we investigate the impact of 10 ALS-linked TBK1 mutations on the critical early stage of mitophagy. We find that both TBK1 recruitment and kinase activity contribute to the clearance of the damaged mitochondria. Furthermore, in neurons, expression of TBK1 mutants alone affects mitochondrial network health. Our investigation utilizes disease-linked mutations to further refine the current model of mitophagy, identifying regulatory crosstalk between the kinases TBK1 and ULK1, and providing insights into the roles of TBK1 in neurodegenerative pathogenesis.<\/jats:p>","DOI":"10.1073\/pnas.2025053118","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T16:57:22Z","timestamp":1623085042000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":104,"title":["ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy"],"prefix":"10.1073","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0719-2901","authenticated-orcid":false,"given":"Olivia","family":"Harding","sequence":"first","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;"},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, MD 20815;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-8604","authenticated-orcid":false,"given":"Chantell S.","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;"},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, MD 20815;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4529-0713","authenticated-orcid":false,"given":"Junqiang","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032;"},{"name":"Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1014-0707","authenticated-orcid":false,"given":"Jonah","family":"Cheung","sequence":"additional","affiliation":[{"name":"Special Projects Group, New York Structural Biology Center, New York, NY 10027;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2722-8633","authenticated-orcid":false,"given":"Tom","family":"Maniatis","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032;"},{"name":"Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027;"},{"name":"New York Genome Center, New York, NY 10013"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5389-4114","authenticated-orcid":false,"given":"Erika L. 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