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These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We\u2019ve previously shown that CK1\u03b4 and CK1\u03b5 phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-\u0394NLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of\n                    <jats:italic>Csnk1e<\/jats:italic>\n                    in the hTDP-43-\u0394NLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of\n                    <jats:italic>Csnk1d<\/jats:italic>\n                    is lethal in mice, and we were unable to test the role of CK1\u03b4 alone. We then targeted both CK1\u03b4 and CK1\u03b5 kinases by way of CK1\u03b4\/\u03b5-selective PF-05236216 inhibitor in the hTDP-43-\u0394NLS mouse model, reasoning that inhibiting CK1\u03b5 alone would be insufficient as shown by our\n                    <jats:italic>Csnk1e<\/jats:italic>\n                    knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1\u03b4\/\u03b5 inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.\n                  <\/jats:p>","DOI":"10.1186\/s40478-024-01902-z","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T09:46:32Z","timestamp":1733305592000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["CK1\u03b4\/\u03b5-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis"],"prefix":"10.1186","volume":"12","author":[{"given":"Vivian I.","family":"Ko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailee","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah Y.","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Pietrasiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukesh","family":"Lulla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guruharsha","family":"Bhat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don W.","family":"Cleveland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Ravits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"1902_CR1","doi-asserted-by":"publisher","first-page":"106050","DOI":"10.1016\/j.nbd.2023.106050","volume":"179","author":"T Afroz","year":"2023","unstructured":"Afroz T, Chevalier E, Audrain M, Dumayne C, Ziehm T, Moser R, Egesipe A-L, Mottier L, Ratnam M, Neumann M, Havas D, Ollier R, Piorkowska K, Chauhan M, Silva AB, Thapa S, St\u00f6hr J, Bavdek A, Eligert V, Adolfsson O, Nelson PT, Porta S, Lee VM-Y, Pfeifer A, Kosco-Vilbois M, Seredenina T (2023) Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS\/FTD. 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