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.