Arimoclomol is a
hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of
heat shock protein expression, but only under conditions of cellular stress.
Arimoclomol has been found to be neuroprotective in a number of
neurodegenerative disease models, including
Amyotrophic Lateral Sclerosis (ALS), and in mutant
Superoxide Dismutase 1 (SOD1) mice that model ALS,
Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of
Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the
neuroprotective effects of enhanced
heat shock protein expression by
Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a
heat shock protein-based
therapy are also discussed in this review. For example,
protein aggregation is a characteristic pathological feature of
neurodegenerative diseases including ALS. Enhanced
heat shock protein expression not only affects
protein aggregation directly, but can also lead to more effective clearance of
protein aggregates via the unfolded protein response, the
proteasome-
ubiquitin system or by autophagy. However, compounds such as
Arimoclomol have effects beyond targeting
protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as
Arimoclomol may be particularly effective in the development of a disease-modifying
therapy for ALS and other
neurodegenerative disorders.