GENETIC MECHANISMS AND THE ROLE OF SUSCEPTIBILITY GENES IN AMYOTROPHIC LATERAL SCLEROSIS: PATHOGENIC PATHWAYS, CLINICAL IMPLICATIONS, AND EMERGING TARGETS

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, leading to paralysis and eventual respiratory failure. While the disease is clinically heterogeneous, genetic factors play a central role in its pathogenesis. Approximately 10% of ALS cases are familial (fALS), with mutations in several key genes including SOD1, C9orf72, TARDBP, and FUS. An increasing body of research has identified additional susceptibility genes and risk loci that contribute to sporadic ALS (sALS) through dysregulation of RNA metabolism, proteostasis, cytoskeletal integrity, and immune responses. This study critically examines the genetic architecture of ALS, explores molecular pathways impacted by pathogenic variants, and evaluates emerging genetic targets for therapeutic intervention. Through comprehensive genomic analysis, we identify novel genes implicated in ALS and provide an integrative model linking genetic variation to neurodegeneration.