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Aggregation of phosphorylated TDP\u201043 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Casein kinase 1\u03b5 (CK1\u03b5) phosphorylates TDP\u201043 at multiple sites, enhances its cytoplasmic aggregation, and modulates its function in tau mRNA processing. To determine roles of TDP\u201043 site\u2010specific phosphorylation in its localization, aggregation, and function in tau mRNA processing, TDP\u201043 was mutated to alanine or aspartic acid at Ser379, Ser403\/404, or Ser409\/410 to block or mimic phosphorylation. Site\u2010specific phosphorylation of TDP\u201043 and its mutants by CK1\u03b5 was studied in vitro and in cultured cells. Cytoplasmic and nuclear TDP\u201043 and phospho\u2010TDP\u201043 were analyzed by western blots. Aggregation of TDP\u201043 was assessed by immunostaining and level of radioimmunoprecipitation assay buffer\u2010insoluble TDP\u201043. Green florescent protein tailed with tau 3\u2032\u2010untranslated region and mini\u2010tau gene pCI\/SI9\u2010LI10 were used to study tau mRNA stability and alternative splicing of tau exon 10. We found that phospho\u2010blocking mutations of TDP\u201043 at Ser379, Ser403\/404, or Ser409\/410 were not effectively phosphorylated by CK1\u03b5. Compared with TDP\u201043, higher level of phosphorylated TDP\u201043 in the cytoplasm was observed. Phospho\u2010mimicking mutations at these sites enhanced cytoplasmic aggregation of TDP\u201043. Green florescent protein expression was not inhibited by phospho\u2010blocking mutants of TDP\u201043, but tau exon 10 inclusion was further enhanced by phospho\u2010blocking mutations at Ser379 and Ser403\/404. Phosphorylation of TDP\u201043 at Ser379, Ser403\/404, or Ser409\/410 primes its phosphorylation by CK1\u03b5, promotes TDP\u201043 cytoplasmic aggregation, and modulates its function in tau mRNA processing in site\u2010specific manner.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15450-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15450","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T18:19:31Z","timestamp":1623262771000},"page":"766-778","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Phosphorylation of trans\u2010active response DNA\u2010binding protein\u2010of 43\u00a0kDa promotes its cytoplasmic aggregation and modulates its function in tau mRNA stability and exon 10 alternative splicing"],"prefix":"10.1111","volume":"158","author":[{"given":"Ruozhen","family":"Wu","sequence":"first","affiliation":[{"name":"Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu Co\u2010innovation Center of Neuroregeneration NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products Department of Biochemistry and Molecular Biology School of Medicine Nantong University Nantong Jiangsu China"},{"name":"Department of Neurochemistry Inge Grundke\u2010Iqbal Research Floor New York State Institute for Basic Research in Developmental Disabilities Staten Island NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingwei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu Co\u2010innovation Center of Neuroregeneration NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products Department of Biochemistry and Molecular Biology School of Medicine Nantong University Nantong Jiangsu China"},{"name":"Department of Neurochemistry Inge Grundke\u2010Iqbal Research Floor New York State Institute for Basic Research in Developmental Disabilities Staten Island NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu Co\u2010innovation Center of Neuroregeneration NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products Department of Biochemistry and Molecular Biology School of Medicine Nantong University Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of 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