Advancements in TDP-43 research: Towards biomarkers and therapeutic targets for amyotrophic lateral sclerosis

• TDP-43 is pivotal in amyotrophic lateral sclerosis (ALS) pathology, showing hyperphosphorylation and aggregation. • ALS diagnosis lacks specific biomarkers, highlighting TDP-43′s potential. • Efforts are ongoing to develop therapies targeting TDP-43 pathology. • Novel models and antibodies are crucial for ALS biomarker development. • Exploring pathways in other diseases can advance ALS treatment. Amyotrophic lateral sclerosis (ALS) remains a devastating neurodegenerative disease characterized by progressive motor neuron degeneration, leading to paralysis and premature death. Despite advances in understanding its pathology, ALS diagnosis and treatment remain primarily symptomatic, lacking disease-specific biomarkers. TAR DNA-binding protein 43 (TDP-43) has emerged as a central player in ALS pathogenesis, undergoing pathological alterations including hyperphosphorylation, truncation, and cytoplasmic aggregation. This article reviews the physiological and pathological roles of TDP-43, its potential as a biomarker, and its candidacy as a therapeutic target. Challenges in detecting pathological forms of TDP-43 in biofluids hinder diagnostic advancements, yet recent research provides insights into its potential diagnostic and prognostic value. Moreover, ongoing efforts aim to develop targeted therapies, including genetic and proteostasis-based approaches, to mitigate TDP-43 pathology and its downstream effects. The article also discusses the need for novel animal models and antibodies to distinguish between pathological and physiological forms of TDP-43 for reliable biomarker development. Looking ahead, the article advocates for both linear and horizontal developments in TDP-43 research to advance ALS diagnosis, prognosis, and treatment paradigms.