HSP27 but not HSP70 has a potent protective effect against α-synuclein-induced cell death in mammalian neuronal cells


Address correspondence and reprint requests to David S. Latchman, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
E-mail: d.latchman@bbk.ac.uk


α-Synuclein is a neuronally expressed protein which is mutated in familial Parkinson's disease. We have previously shown that disease-associated mutants of α-synuclein cause enhanced neuronal cell death in response to a variety of stimuli, whereas wild-type α-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 α-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 α-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.