{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:15:43Z","timestamp":1791220543280,"version":"4.1.0"},"reference-count":36,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6615","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2022,10,7]]},"abstract":"<jats:p>\n                    Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the\n                    <jats:italic>C9orf72<\/jats:italic>\n                    gene and mutations in the TANK-binding kinase 1 (\n                    <jats:italic>TBK1<\/jats:italic>\n                    ) gene. We found that TBK1 is phosphorylated in response to\n                    <jats:italic>C9orf72<\/jats:italic>\n                    poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg\n                    <jats:sup>228<\/jats:sup>\n                    \u2192His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between\n                    <jats:italic>C9orf72<\/jats:italic>\n                    ,\n                    <jats:italic>TBK1<\/jats:italic>\n                    , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.\n                  <\/jats:p>","DOI":"10.1126\/science.abq7860","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T14:00:46Z","timestamp":1665064846000},"page":"94-99","source":"Crossref","is-referenced-by-count":84,"title":["Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration"],"prefix":"10.1126","volume":"378","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-4904","authenticated-orcid":true,"given":"Wei","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4327-6114","authenticated-orcid":true,"given":"Tiffany W.","family":"Todd","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8230-1549","authenticated-orcid":true,"given":"Caroline Y.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimei","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1234-7103","authenticated-orcid":true,"given":"Karen","family":"Jansen-West","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4644-7265","authenticated-orcid":true,"given":"Lillian M.","family":"Daughrity","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6579-4356","authenticated-orcid":true,"given":"Jinyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5067-8579","authenticated-orcid":true,"given":"Yuka","family":"Koike","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishe","family":"Kurti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8441-7801","authenticated-orcid":true,"given":"Monica","family":"Castanedes-Casey","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"del Rosso","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."},{"name":"Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0190-0089","authenticated-orcid":true,"given":"Judith A.","family":"Dunmore","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desiree","family":"Zanetti Alepuz","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1725-9866","authenticated-orcid":true,"given":"Bj\u00f6rn","family":"Oskarsson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-7917","authenticated-orcid":true,"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."},{"name":"Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5963-8442","authenticated-orcid":true,"given":"Casey N.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."},{"name":"Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4894-4858","authenticated-orcid":true,"given":"Mercedes","family":"Prudencio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."},{"name":"Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7335-2627","authenticated-orcid":true,"given":"Tania F.","family":"Gendron","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."},{"name":"Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Fryer","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."},{"name":"Department of Neuroscience, Mayo Clinic, Scottsdale, AZ 85259, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9900-4313","authenticated-orcid":true,"given":"Yong-Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA."},{"name":"Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-129X","authenticated-orcid":true,"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 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