Neurobiology of Brain Disorders (Second Edition) - Chapter 15: Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system characterized by focal and then generalized weakness leading to paralysis and death from respiratory failure. Symptoms arise from the loss of corticospinal (upper) and brainstem and spinal (lower) motor neurons. The cause of sporadic ALS (sALS) is unknown. Investigations of the 10% of cases that are familial (fALS) have identified over 30 genes whose mutations predispose to ALS. Expression of mutant ALS genes in rodents and cells has generated models that facilitate identification of molecular pathways in ALS. Three pathological processes appear to be central in this disease: (1) conformational instability and aberrant trafficking of critical proteins; (2) perturbations of processing of RNA and RNA-binding proteins; and (3) disruption of homeostasis. Related events include protein aggregation and disturbances of mitochondria, neuronal excitability and axonal transport. Elucidation of these pathways and events provides targets for treatment development.