| Inhibitors of heat shock protein 90 are being developed and tested as anticancer drugs. Conversely, inhibition of HSP90 shows protective effects in neuronal culture models of excitotoxicity and oxidative stress and in animal models of motor neuron disease. Here, we study the effects of HSP90 inhibition on motor neuron survival in culture, and we propose that HSP90 inhibition prevents death in a trophic factor deprivation model. We tested the effects of geldanamycin on HSP90 inhibition by using high throughput survival analysis. Interestingly, high picomolar concentrations of geldanamycin induced apoptosis in our model. Induction of motor neuron apoptosis by HSP90 requires Fas activation, which is followed by activation of caspases, but not p38 MAP kinase activation or nitric oxide production. Activation of Fas by geldanamycin in motor neurons is preceded by the dephosphorylation of AKT and the upregulation of Fas ligand transcription and translation. Forced expression of constitutively active PI3 kinase prevented cell death induced by geldanamycin. These results suggest that motor neuron high susceptibility to geldanamycin is due to the dependence of motor neurons on the PI3K/AKT for survival in culture. |
