Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive, fatal neurodegenerative disorder affecting motor neurons. It is characterized by the degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy, and paralysis. ALS can present in various clinical forms, including progressive muscular atrophy, primary lateral sclerosis, bulbar ALS, and pseudobulbar palsy. Genetic factors play a significant role in ALS, with about 10% of cases being familial and inherited as dominant traits. Over 50 genes have been implicated in ALS, with mutations in genes such as SOD1, C9ORF72, TARDBP, and FUS being particularly associated with the disease. These mutations often affect RNA metabolism, protein homeostasis, and cytoskeletal dynamics. ALS pathology includes the degeneration of motor neurons and the accumulation of ubiquitinated inclusions, particularly TDP-43 inclusions. The disease is also associated with non-cell-autonomous effects, where glial cells contribute to the progression of the disease. Mutant SOD1, for example, can cause toxicity through misfolding and aggregation, leading to the formation of inclusions. Additionally, C9ORF72 mutations are linked to the expansion of hexanucleotide repeats, which can lead to the production of dipeptide repeat proteins (DPRs) and the formation of pathological RNA foci. The pathogenesis of ALS involves multiple mechanisms, including ER stress, impaired protein degradation, and defects in nucleocytoplasmic trafficking. RNA metabolism is also a key aspect, with RNA-binding proteins such as TDP-43, FUS, and hnRNPA1 playing critical roles. Phase separation of these proteins can lead to the formation of membrane-less organelles, which may contribute to the disease. Additionally, prion-like propagation of misfolded proteins may facilitate the spread of pathology. Therapeutic approaches for ALS are being explored, including targeting the C9ORF72 gene through antisense oligonucleotides and the development of transgenic mouse models. Despite significant progress in understanding the genetic and molecular basis of ALS, the exact mechanisms of toxicity and effective therapies remain areas of active research. The complexity of ALS pathology presents challenges in developing targeted treatments, but advances in genetic and molecular biology offer promising avenues for future research and therapeutic intervention.Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive, fatal neurodegenerative disorder affecting motor neurons. It is characterized by the degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy, and paralysis. ALS can present in various clinical forms, including progressive muscular atrophy, primary lateral sclerosis, bulbar ALS, and pseudobulbar palsy. Genetic factors play a significant role in ALS, with about 10% of cases being familial and inherited as dominant traits. Over 50 genes have been implicated in ALS, with mutations in genes such as SOD1, C9ORF72, TARDBP, and FUS being particularly associated with the disease. These mutations often affect RNA metabolism, protein homeostasis, and cytoskeletal dynamics. ALS pathology includes the degeneration of motor neurons and the accumulation of ubiquitinated inclusions, particularly TDP-43 inclusions. The disease is also associated with non-cell-autonomous effects, where glial cells contribute to the progression of the disease. Mutant SOD1, for example, can cause toxicity through misfolding and aggregation, leading to the formation of inclusions. Additionally, C9ORF72 mutations are linked to the expansion of hexanucleotide repeats, which can lead to the production of dipeptide repeat proteins (DPRs) and the formation of pathological RNA foci. The pathogenesis of ALS involves multiple mechanisms, including ER stress, impaired protein degradation, and defects in nucleocytoplasmic trafficking. RNA metabolism is also a key aspect, with RNA-binding proteins such as TDP-43, FUS, and hnRNPA1 playing critical roles. Phase separation of these proteins can lead to the formation of membrane-less organelles, which may contribute to the disease. Additionally, prion-like propagation of misfolded proteins may facilitate the spread of pathology. Therapeutic approaches for ALS are being explored, including targeting the C9ORF72 gene through antisense oligonucleotides and the development of transgenic mouse models. Despite significant progress in understanding the genetic and molecular basis of ALS, the exact mechanisms of toxicity and effective therapies remain areas of active research. The complexity of ALS pathology presents challenges in developing targeted treatments, but advances in genetic and molecular biology offer promising avenues for future research and therapeutic intervention.