title: Hsp27 and Hsp70 administered in combination have a potent protective effect against FALS-associated SOD1-mutant-induced cell death in mammalian neuronal cells.
abstract: 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.
authors.affiliation: Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Yogesh J K
authors.initials: YJ
authors.lastname: Patel
authors.forename: Martin D
authors.initials: MD
authors.lastname: Payne Smith
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Belleroche
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D006224:Cricetinae; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004195:Disease Models, Animal; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology*; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage*; D006360:Heat-Shock Proteins / Q000008:administration & dosage*; D020287:In Situ Nick-End Labeling / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D009363:Neoplasm Proteins / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D049452:Green Fluorescent Proteins; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019311:Staurosporine