Genetic aspects of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a progressive, incurable neurodegenerative disease characterized by motor neuron loss and the development of paralysis and skeletal muscle atrophy. This review focuses on the genetic aspects of amyotrophic lateral sclerosis, with an emphasis on four key genes—C9orf72, SOD1, TARDBP, and FUS—mutations in which account for most familial cases and represent important targets for therapeutic development. The genetic architecture of amyotrophic lateral sclerosis is complex and predominantly determined by monogenic inheritance of mutations. To date, more than 40 amyotrophic lateral sclerosis-associated genes have been identified, differing in prevalence, inheritance patterns, and penetrance. Mutations in C9orf72, SOD1, TARDBP, and FUS lead to disruption of critically important cellular processes. These processes include protein homeostasis, RNA metabolism, mitochondrial function, autophagy, cytoskeletal integrity, and DNA repair. Despite considerable progress, genetic predisposition explains only a portion of amyotrophic lateral sclerosis cases, underscoring the need for further investigation of environmental factors, epigenetic modifications, and accompanying pathophysiologic processes such as oxidative stress and inflammation. Comprehensive studies of molecular-genetic and pathophysiologic mechanisms is essential for the development of effective strategies for early diagnosis and treatment of amyotrophic lateral sclerosis.