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In tauopathies, including Alzheimer\u2019s disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a <jats:italic>Drosophila melanogaster<\/jats:italic> model, transgenic flies neuronally expressing active <jats:italic>Drosophila<\/jats:italic> Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.<\/jats:p>","DOI":"10.1038\/s41380-020-01003-y","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T13:05:48Z","timestamp":1610715948000},"page":"5542-5556","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation"],"prefix":"10.1038","volume":"26","author":[{"given":"Jisu","family":"Park","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunwoo","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Doo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5112-0104","authenticated-orcid":false,"given":"Seo-Hyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youbin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5618-9370","authenticated-orcid":false,"given":"Youngdae","family":"Gwon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong Young","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8681-1597","authenticated-orcid":false,"given":"Sung-Hye","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Won Do","family":"Heo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9686-3120","authenticated-orcid":false,"given":"Yong-Keun","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,1,15]]},"reference":[{"key":"1003_CR1","doi-asserted-by":"publisher","first-page":"4441","DOI":"10.1073\/pnas.0709259105","volume":"105","author":"WS Liang","year":"2008","unstructured":"Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, et al. 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