Hsp27 and Hsp70 administered in combination have a potent protective effect against FALS-associated SOD1-mutant-induced cell death in mammalian neuronal cells.

Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disorder characterised by the death of motor neurons in the cortex, brainstem, and spinal cord; resulting in progressive muscle weakness, atrophy, and death from respiratory paralysis, usually within 3-5 years of symptom onset. Approximately 10% of ALS cases are familial (FALS). Mutations in superoxide dismutase-1 (SOD1) cause approximately 20% of FALS cases and there is overwhelming evidence that a toxic gain of function is the cause of the disease. We have previously shown that FALS-associated SOD1 disease mutants enhanced neuronal death in response to a wide range of stimuli tested whereas wt-SOD1 protected against all insults. We demonstrate for the first time that over-expression of either heat shock protein Hsp27 or Hsp70 has a protective effect against SOD1 disease associated mutant-induced cell death. However, over-expression of Hsp27 and Hsp70 together has a greater potent anti-apoptotic effect, than when expressed singly, against the damaging effects of mutant SOD1. Our results indicate that FALS-associated SOD1 disease mutants possess enhanced death-inducing properties and lead to increased apoptosis which can be prevented by either the use of specific caspase inhibitors or Hsp27 and/or Hsp70 over-expression. This potent protective effect of Hsp27 and Hsp70 against the FALS-associated SOD1 disease mutants may be of potential therapeutic importance.