TDP-43: A COMMON THREAD IN NEURODEGENERATION AND CANCER

TDP-43, a multifunctional RNA-binding protein encoded by the TARDBP gene, plays critical roles in RNA metabolism, including splicing, transport, and stability. Dysregulation of TDP-43 is implicated in a range of neurodegenerative diseases, most notably Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Recent evidence also identifies TDP-43 as a significant contributor to oncogenesis, with aberrant expression linked to various cancers, including breast, lung, and colorectal cancer. This review explores the dual role of TDP-43 in neurodegeneration and cancer, highlighting its structural domains, pathological aggregation mechanisms, and regulatory functions in cellular processes. We provide a detailed analysis of TDP-43’s involvement in neurodegenerative disorders through mechanisms such as mis localization, gain- and loss-of-function mutations, and interactions with stress granules, as well as its contribution to cancer progression via regulation of oncogenes and tumor suppressors. Furthermore, we discuss therapeutic strategies targeting TDP-43 in both disease contexts, including RNA-based therapies, molecular chaperones, and modulation of autophagy and cell signalling pathways. By integrating current research on TDP-43’s molecular interactions and pathogenic roles, this review underscores the need for further investigation into its dual functions and therapeutic potential in treating both neurodegenerative diseases and cancer.