The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol

Pharmacol Ther. 2014 Jan;141(1):40-54. doi: 10.1016/j.pharmthera.2013.08.003. Epub 2013 Aug 23.


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.

Keywords: 17-AAG; 17-N-Allylamino-17-demethoxygeldanamycin; 78kDa glucose-regulated protein; ALS; ATF6; Activating transcription factor 6; Amyotrophic Lateral Sclerosis; Arimoclomol; BIP; Binding immunoglobulin protein; C/EBP homologous protein (CHOP); C9ORF72; CHIP; CHOP; COX-2; Chromosome 9 open reading frame 72; DNA; Deoxyribonucleic Acid; ER; Endoplasmic Reticulum; FTD; FUS; Familial Amyotrophic Lateral Sclerosis; Fas/FasL; Frontotemporal Dementia; Fused in Sarcoma; Grp78; HSEs; HSFs; HSR; Heat Shock Cognate; Heat Shock Elements; Heat Shock Factors; Heat Shock Proteins; Heat Shock Response; Heat shock proteins; Heat shock response; Hsc; Hsps; IRE1α; Kilodalton; NF-κB; Neurodegeneration; PERK; RNA; ROS; Reactive Oxygen Species; Ribonucleic Acid; SOD1; SOD1 mice; Sporadic Amyotrophic Lateral Sclerosis; Superoxide dismutase 1; TDP-43; TNF-α; Tar DNA-binding protein 43; The carboxyl terminus of heat shock protein 70-interacting protein; Tumor Necrosis Factor-α; UPR; Unfolded Protein Response; Wild-type SOD1; a trans-membrane receptor of the tumor necrosis factor (TNF) receptor superfamily/the ligand for Fas; cyclooxygenase-2; endoplasmic reticulum to nucleus signaling 1 α; fALS; kDa; mSOD1; mutant SOD1; nuclear factor kappa-light-chain-enhancer of activated B cells; protein kinase RNA-like endoplasmic reticulum kinase; recombinant human Hsp70 protein; rhHsp70; sALS; wtSOD1.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Enzyme Induction / drug effects
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / drug effects*
  • Heat-Shock Proteins / metabolism*
  • Heat-Shock Response / drug effects
  • Humans
  • Hydroxylamines / pharmacology*
  • Hydroxylamines / therapeutic use*
  • Models, Biological
  • Molecular Targeted Therapy / methods
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use


  • Heat-Shock Proteins
  • Hydroxylamines
  • Neuroprotective Agents
  • arimoclomol