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Aggregated TDP\u201043 in these diseases is hyperphosphorylated in its C\u2010terminal intrinsically disordered region, while physiological TDP\u201043 is normally unphosphorylated. Whether TDP\u201043 phosphorylation is a pathological driver, or rather a protective antagonist of TDP\u201043 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP\u201043 phosphorylation in disease and the kinases and phosphatases that regulate this post\u2010translational modification. We discuss how TDP\u201043 phosphorylation is thought to shape TDP\u201043's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP\u201043 phase separation and aggregation, and speculate about a potential role of condensates in TDP\u201043 phosphorylation.<\/jats:p>","DOI":"10.1002\/bies.70084","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T07:00:21Z","timestamp":1762153221000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["TDP\u201043 Phosphorylation: Pathological Modification or Protective Factor Antagonizing TDP\u201043 Aggregation in Neurodegenerative Diseases?"],"prefix":"10.1002","volume":"48","author":[{"given":"Simone","family":"Mosna","sequence":"first","affiliation":[{"name":"Institute of Molecular Physiology Faculty of Biology Johannes Gutenberg University  Mainz Germany"},{"name":"International PhD Programme (IPP) of IMB Mainz  Mainz 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