Oxidative Stress in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a prototypic, age-dependent neurodegenerative disorder caused by the degeneration of motor neurons in cortex, brainstem, and spinal cord with an incidence of 1 in 10000.1 It typically afflicts individuals in middle adult life, leading to paralysis and death within 3 to 5 years. Approximately 10% of cases are familial (FALS),2 and in a subset of cases, mutations in the CuZnSOD gene, which encodes CuZnSOD, have been demonstrated.3 In both sporadic and familial forms clinical courses are highly similar.4 The disease usually begins asymmetrically and distally in one limb, most commonly the leg, and then appears to spread within the neuraxis to involve contiguous groups of motor neurons. Pathologically, ALS is distinguished by atrophy and death of the affected neurons, with dissolution of both cytoplasm and nuclei. The motor neuron death process appears to be cell autonomous; autopsy studies reveal no evidence that other cell types participate in killing motor neurons. Many affected neurons demonstrate evidence of cytoskeletal pathology in the form of accumulations of neurofilaments,5 both within the neuronal cell body and in axons. Aggregates of ubiquitinated, unidentified proteins are also seen, as is subtle proliferation of glial cells.6 The motor neurons are described as the final common pathway of the central nervous system, transforming neuronal action into activation of muscle. The neuromuscular junction distinguishes lower motor neurons from all other neurons and may contribute to the selective vulnerability of motor neurons in ALS. ALS is characterized principally by degeneration of large motor neurons in the ventral horn of the spinal cord and by degeneration of upper motor neurons in the cerebral cortex. Because muscle fibers are innervated by only a single motor neuron, other motor neurons normally rewire to the muscle fiber to take over the function of a damaged motor neuron. Muscle from ALS patients contains far more neuromuscular junctions than normal muscle. Remodeling of synapses and motor endplates may cause subsequent injury of adjacent motor neurons.KeywordsNitric OxideAmyotrophic Lateral SclerosisMotor NeuronAmyotrophic Lateral Sclerosis PatientMotor Neuron DiseaseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.