Advances and Challenges in Understanding the Multifaceted Pathogenesis of Amyotrophic Lateral Sclerosis

Swiss Med Wkly. 2015 Jan 30;145:w14054. doi: 10.4414/smw.2015.14054. eCollection 2015.

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, which primarily affects motor neurons leading to progressive paralysis and death within a few years from onset. The pathological hallmark of ALS is the presence of cytoplasmic ubiquitinated protein inclusions in motor neurons and glial cells primarily in the spinal cord. While the vast majority of ALS occurs sporadically (sALS), in ~10% of cases, called familial ALS (fALS), there is clear indication of genetic inheritance. In the last decade, enormous progress was made in unravelling the aetiology of the disease, with the identification of ALS-causing mutations in new genes, as well as key molecular players involved in the origin or progression of ALS. However, much more needs to be done, as the pathogenic mechanisms triggered by a genetic or sporadic event leading to cytotoxicity and neuronal cell death are still poorly understood. The recent discoveries offer new possibilities for devising experimental animal and cellular models, which will hopefully contribute to the development of new techniques for early diagnosis and the identification of therapeutic targets for ALS. Here we review the current understanding of the aetiology, genetics, and pathogenic factors and mechanisms of ALS. We also discuss the challenges in deciphering ALS pathogenesis that result from the high complexity and heterogeneity of the disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Humans
  • Mice
  • Middle Aged
  • Mutation / genetics
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • C9orf24 protein, human
  • DNA-Binding Proteins
  • FUS protein, human
  • Nuclear Proteins
  • RNA-Binding Protein FUS
  • SOD1 protein, human
  • Transcription Factors
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1