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The 27-kDa heat shock protein (HSP27) has a potent ability to increase cell survival in response to a wide range of cellular challenges. In order to investigate the mode of action of HSP27 in vivo, we have developed transgenic lines, which express human HSP27 at high levels throughout the brain, spinal cord, and other tissues. In view of the particular property of HSP27 compared with other HSPs to protect neurons against apoptosis, we have tested these transgenic lines in a well established in vivo model of neurotoxicity produced by kainic acid, where apoptotic cell death occurs. Our results demonstrate for the first time the marked protective effects of HSP27 overexpression in vivo, which significantly reduces kainate-induced seizure severity and mortality rate (>50%) in two independent lines and markedly reduces neuronal cell death in the CA3 region of hippocampus. This reduced seizure severity in HSP27 transgenic animals was associated with a marked attenuation of caspase 3 induction and apoptotic features. These studies clearly demonstrate that HSP27 has a major neuroprotective effect in the central nervous system in keeping with its properties demonstrated in culture and highlight an early stage in the cell death pathway that is affected by HSP27.

Original publication

DOI

10.1074/jbc.M207073200

Type

Journal article

Journal

J Biol Chem

Publication Date

30/05/2003

Volume

278

Pages

19956 - 19965

Keywords

Animals, Behavior, Animal, Caspase 3, Caspases, Cell Death, Enzyme Activation, Heat-Shock Proteins, Hippocampus, In Situ Hybridization, Kainic Acid, Mice, Mice, Transgenic, Neoplasm Proteins, Neuroprotective Agents, Seizures