Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.