Molecular dysregulation in Amyotrophic-lateral sclerosis: investigating TDP-43, target genes, and therapeutic strategies
Charani Nakka
02/02/2026
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the selective loss of motor neurons, leading to paralysis and eventual death. TAR DNA-binding protein 43 (TDP-43) has emerged as a central pathological hallmark in both sporadic and familial ALS cases. Current research suggests that abnormal TDP-43 localization disrupts critical RNA-binding functions, leading to both a loss of nuclear RNA-binding function and a gain of toxic cytoplasmic aggregation, driving ALS’s progressive neurodegeneration, synaptic dysfunction, and neuronal death This narrative review evaluates the molecular mechanisms by which TDP-43 contributes to neurodegeneration, emphasizing RNA dysregulation, protein aggregation, and gene interactions such as those involving Ataxin-2. Furthermore, TDP-43 dysfunction disrupts RNA splicing, transport, and translation, emphasizing its downstream effects on genes such as STMN2 and UNC13A, which are crucial for axonal integrity and synaptic transmission. By synthesizing recent findings, this review highlights promising therapeutic directions, including antisense oligonucleotides targeting Ataxin-2, small molecules inhibiting TDP-43 aggregation, and CRISPR-based gene-editing strategies designed to restore homeostatic RNA regulation, offering a path toward disease-targeting interventions for ALS TDP-43 pathology. Despite these advances, translation from preclinical to clinical efficacy remains limited, reflecting the need for integrative therapeutic approaches that address the multifactorial nature of ALS pathology. Collectively, this review underscores TDP-43’s pivotal role in disease progression and identifies molecular pathways that may inform the next generation of targeted therapies.