TAR DNA-binding protein 43 (TDP-43) is a multifunctional DNA/RNA-binding protein whose abnormal phosphorylation and aggregation are central to the pathogenesis of several neurodegenerative diseases. TDP-43 proteinopathy, characterized by hyperphosphorylation and cytoplasmic accumulation, is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and is frequently observed in Alzheimer's disease. The phosphorylation state of TDP-43 is dynamically regulated by a network of protein kinases—including CK1, GSK3β, CDC7, and PKA—and counterbalanced by phosphatases such as PP2A and PP1; however, the precise molecular mechanisms governing this equilibrium in disease remain incompletely understood. Notably, phosphorylated TDP-43 acquires prion-like properties, enabling self-templated aggregation and cell-to-cell propagation, which amplifies pathology and drives disease progression. These insights have catalyzed the development of therapeutic strategies aimed at modulating TDP-43 phosphorylation, with kinase inhibitors and phosphatase enhancers emerging as promising candidates for targeting TDP-43 proteinopathies. This review integrates current knowledge on the regulatory networks controlling TDP-43 phosphorylation, examines its role in prion-like spread, and evaluates emerging therapeutic approaches aimed at mitigating TDP-43-mediated neurodegeneration.
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