SOD1 Mutations in Amyotrophic Lateral Sclerosis

Introduction

Amyotrophic lateral sclerosis (ALS), the most common adultonset motor neuron disease, is a progressive and fatal disorder characterized by neurodegeneration of motor neurons in the motor cortex, brain stem, and spinal cord 1. Although motor neurons are selectively affected by degeneration and death, increasing evidence indicates that non-neuronal neighboring cell types contribute to pathogenesis and disease progression 2, 3. Motor neuron degeneration results in progressive weakness of bulbar, thoracic, abdominal, and limb muscles. Dysfunction of upper motor neurons (UMN) in the motor cortex leads to hyperreflexia, extensor plantar response, and increased muscle tone, whereas dysfunction of lower motor neuron (LMN) in the brainstem and spinal cord triggers generalized weakness, hyporeflexia, muscle atrophy, muscle cramps, and fasciculations 1. Symptoms present in early disease may vary. Affected individuals most often present with asymmetrical distal onset in a limb with both UMN and LMN signs from the onset (classical Charcot ALS). Patients with bulbar-onset ALS typically have slurred speech and difficulty swallowing, and the condition is designated progressive bulbar palsy (PBP). Limbs symptoms in the majority of cases will occur within 1–2 years. During the course of the disease, most cases become generalized with a combination of both LMN and UMN signs affecting spinal and brainstem regions 4.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder characterized by degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord. Most cases of ALS appear sporadically but about 1–13.5% of patients have a family history of ALS. Although the precise cause for the majority of cases is still unknown, mutations in the gene encoding for copper–zinc superoxide dismutase (SOD1) have been found in 12–23% of familial cases of the disease. Currently, more than 150 different SOD1 gene mutations have been identified in ALS patients most of which with autosomal dominant transmission. Occasionally, specific mutations are associated with a particular phenotype. Some SOD1 mutations occur as recurrent or founder mutations with a different geographic distribution. The discovery of mutations in the SOD1 gene has marked a change in ALS research and enabled the development of novel experimental rodent models to investigate the pathogenesis of familial ALS. However, the mechanism by which mutant SOD1 causes neural death remains elusive. Several lines of evidence suggest that ALS is a protein-folding disease and the increased propensity of mutant SOD1 to form aggregates may confer toxicity in motor neurons. Despite the apparent selectivity for motor neurons, recent data indicate that non-neuronal cell types contribute to pathogenesis and disease progression.

Keywords

Amyotrophic lateral sclerosis, familial and sporadicals, superoxide dismutase 1 (SOD1) Gene, mutation, founder effect, animal models, protein aggregation