HSP27 but not HSP70 has a potent protective effect against alpha-synuclein-induced cell death in mammalian neuronal cells.
alpha-Synuclein is a neuronally expressed protein which is mutated in familial Parkinson's disease. We have previously shown that disease-associated mutants of alpha-synuclein cause enhanced neuronal cell death in response to a variety of stimuli, whereas wild-type alpha-synuclein has a protective effect against some stimuli, whilst enhancing the death response to others. We demonstrate, for the first time, that over-expression of the heat shock protein HSP27 has a potent protective anti-apoptotic effect against the damaging effects of wild-type and particularly of mutant alpha-synuclein. In contrast, HSP70 has some protective effect against the damaging effect of the wild-type protein, but has no effect against the mutant proteins, whilst HSP56 has no protective effect in this system. Our results indicate that disease-associated mutants of alpha-synuclein enhance its death-inducing properties and lead to increased apoptosis, which can be mitigated by either the use of specific caspase inhibitors or HSP27 over-expression. This potent protective effect of HSP27 against the mutant and wild-type proteins may be of potential therapeutic importance.
Medical Molecular Biology Unit, Institute of Child Health, University College, London, UK.
Alexandra
A
Zourlidou
Martin D
MD
Payne Smith
David S
DS
Latchman
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D061945:Caspase Inhibitors; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D006224:Cricetinae; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019610:Cytoprotection / Q000235:genetics; D004298:Dopamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D006360:Heat-Shock Proteins; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D018832:Molecular Chaperones; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D051843:Synucleins; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D051844:alpha-Synuclein
D061945:Caspase Inhibitors; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C486114:Hspb1 protein, rat; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D019311:Staurosporine; D004298:Dopamine