Journal Article

Emerging mechanisms of molecular pathology in ALS

Brown, Robert H., Ghasemi, Mehdi, Peters, Owen M.

2015

Overview

Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable.

• Publisher: American Society for Clinical Investigation
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Amyotrophic Lateral Sclerosis - therapy / Analysis / Animals / Axonal Transport / Axons - ultrastructure / Binding proteins / Biomedical research / Cytoskeleton - ultrastructure / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Gene mutations / Genetic aspects / Genetic Association Studies / Genetic Therapy / Health aspects / Humans / Inflammation / Mice / Mice, Transgenic / Molecular Targeted Therapy / Motor Neurons - chemistry / Motor Neurons - pathology / Mutation / Nerve Tissue Proteins - chemistry / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neuroglia - immunology / Oxidative Stress / Pathology / Physiological aspects / Protein Aggregation, Pathological / Protein Processing, Post-Translational / Proteolysis / Review / Risk factors / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Rodents / Superoxide Dismutase - deficiency / Superoxide Dismutase - genetics / Superoxide Dismutase-1 / Ubiquitination