Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS

J Neurochem. 2008 Oct;107(2):339-50. doi: 10.1111/j.1471-4159.2008.05595.x. Epub 2008 Sep 2.


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motoneuron degeneration, resulting in muscle paralysis and death, typically within 1-5 years of diagnosis. Although the pathogenesis of ALS remains unclear, there is evidence for the involvement of proteasome dysfunction and heat shock proteins in the disease. We have previously shown that treatment with a co-inducer of the heat shock response called arimoclomol is effective in the SOD(G93A) mouse model of ALS, delaying disease progression and extending the lifespan of SOD(G93A) mice (Kieran et al. 2004). However, this previous study only examined the effects arimoclomol when treatment was initiated in pre- or early symptomatic stages of the disease. Clearly, to be of benefit to the majority of ALS patients, any therapy must be effective after symptom onset. In order to establish whether post-symptomatic treatment with arimoclomol is effective, in this study we carried out a systematic assessment of different treatment regimes in SOD(G93A) mice. Treatment with arimoclomol from early (75 days) or late (90 days) symptomatic stages significantly improved muscle function. Treatment from 75 days also significantly increased the lifespan of SOD(G93A) mice, although treatment from 90 days has no significant effect on lifespan. The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. Interestingly, this up-regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin-positive aggregates in the spinal cord of treated SOD(G93A) mice, suggesting that arimoclomol directly effects protein aggregation and degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Female
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Hydroxylamines / therapeutic use*
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / physiology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Spinal Cord / pathology
  • Statistics, Nonparametric
  • Superoxide Dismutase / genetics
  • Survival Analysis
  • Ubiquitin / metabolism


  • HSP70 Heat-Shock Proteins
  • Hydroxylamines
  • Ubiquitin
  • SOD1 G93A protein
  • Superoxide Dismutase
  • arimoclomol