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Hsp27 and Hsp70 administered in combination have a potent protective effect against FALS-associated SOD1-mutant-induced cell death in mammalian neuronal cells (2005)

Patel,
Y.J.,
Payne,
Smith,
M.D.,
De,
Belleroche J.,
Latchman,
D.S.

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

Publication details

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Repository	UCL Research Publications Index (MyOPIA) (United Kingdom)
Keywords	1, A, acid, administration & dosage, AGENT, AGENTS, ALL, AMINO, amino acid, Amino Acid Chloromethyl Ketones, Amino-acid, Amyotrophic Lateral Sclerosis, Analysis of Variance, AND, animals, Animals,Newborn, APOPTOSIS, ARTICLE, Atrophy, Blotting,Western, cell, Cell Death, CELL-DEATH, CELLS, Cells,Cultured, CHILD, child health, COMBINATION, Comparative Study, CORD, cortex, Cricetinae, CULTURE, Culture Media, Culture Media,Serum-Free, cytology, DEATH, DISEASE, Disease Models,Animal, DISORDER, DRUG, Drug Combinations, drug effects, Drug Interactions, enzyme, Enzyme Inhibitors, FAMILIAL, FOR, FUNCTION, Ganglia,Spinal, Genetic, Genetic Vectors, genetics, Green Fluorescent Proteins, HEALTH, HEAT, heat shock protein, Heat-shock, Heat-Shock Proteins, HIV-1, hsp70, HSP70 Heat-Shock Proteins, IM, In Situ Nick-End Labeling, INHIBITOR, inhibitors, IS, JOURNAL, LA, LONDON, METABOLISM, METHODS, MOLECULAR, Molecular Biology, Motor Neurons, MUSCLE, Muscle Weakness, Mutagenesis, Mutant, MUTATION, MUTATIONS, Neoplasm Proteins, Neuron, NEURONS, Neuroprotective Agents, OF, ONSET, OVEREXPRESSION, Pathology, pharmacology, PHYSIOLOGY, physiopathology, prevention & control, PROTEIN, Proteins, RAT, RATS, Research Support,Non-U.S.Gov't, RESPIRATORY, Respiratory Paralysis, Result, SCLEROSIS, Shock, SPINAL CORD, Staurosporine, SUPEROXIDE, Superoxide Dismutase, THE, TIME, Time Factors, Transfection, UK, unit, Universities, Use
Type	JOUR
Relation	256-274, 2, Molecular Brain Research, 134