Taking a risk: a therapeutic focus on ataxin-2 in amyotrophic lateral sclerosis?

Trends Mol Med. 2014 Jan;20(1):25-35. doi: 10.1016/j.molmed.2013.09.001. Epub 2013 Oct 16.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of lower and upper motor neurons leading to progressive muscle weakness and respiratory insufficiency. No treatment is currently available to cure ALS. Recent progress has led to the identification of several novel genetic determinants of this disease, including repeat expansions in the ataxin-2 (ATXN2) gene. Ataxin-2 is mislocalized in ALS patients and represents a relatively common susceptibility gene in ALS, making it a promising therapeutic target. In this review, we summarize genetic and pathological data implicating ataxin-2 in ALS, discuss potential disease mechanisms linked to altered ataxin-2 localization or function, and propose potential strategies for therapeutic intervention in ALS based on ataxin-2.

Keywords: FUS; TDP-43; amyotrophic lateral sclerosis; antisense oligonucleotide therapy; ataxin-2; neurodegeneration.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / therapy
  • Animals
  • Ataxins
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / toxicity
  • Humans
  • Motor Neurons / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Peptides
  • Protein Binding
  • RNA / genetics
  • RNA / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Risk Factors
  • Trinucleotide Repeat Expansion


  • Ataxins
  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Peptides
  • Receptors, Cytoplasmic and Nuclear
  • polyglutamine
  • RNA