Emerging mechanisms of molecular pathology in ALS

J Clin Invest. 2015 May;125(5):1767-79. doi: 10.1172/JCI71601. Epub 2015 May 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / therapy
  • Animals
  • Axonal Transport
  • Axons / ultrastructure
  • Cytoskeleton / ultrastructure
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Genetic Association Studies
  • Genetic Therapy
  • Humans
  • Inflammation
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Motor Neurons / chemistry
  • Motor Neurons / pathology
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuroglia / immunology
  • Oxidative Stress
  • Protein Aggregation, Pathological
  • Protein Processing, Post-Translational
  • Proteolysis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Superoxide Dismutase / deficiency
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Ubiquitination


  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1