The role of creb in neurodegenerative diseases
The cAMP response element binding protein (CREB) is an essential regulator of stimulus-driven gene expression, best described for its role in immediate-early gene transcription and neuronal plasticity. Together with the closely related cAMP response element modulator (CREM), it has been shown to be necessary for survival of specific types of forebrain neurons, most notably in the striatum or hippocampus, but dispensable in other neuron types, like the monoamine cells. This selective role of CREB in neuronal survival prompted investigation into its involvement in neurodegenerative disorders, particularly Huntington’s and Niemann-Pick type C diseases. In order to assess the role of CREB-dependent transcription in triggering neuronal death, using the Cre/loxP system we have generated mice with a selective ablation of CREB in the forebrain and deletion of CREM. Gene expression profiling in the striatum and hippocampus of double-mutant mice revealed that neurodegeneration was accompanied with strong increase in abundance of transcripts associated with activation of the glia, but also changed expression of genes participating in sterol metabolism. Moreover, comparison of expression profiles with those reported in other models of striatal neurodegeneration reveals a common pattern of changes, involving several genes associated with the medium spiny neurons of the striatum. Interestingly, in a mutant mouse with a single CREM allele, no neurodegeneration was observed, and their expression profile allows to identify key CREB/CREM-dependent transcripts essential for cell survival. These observations help to understand the roles of CREB and CREM in neuronal homeostasis and their involvement in neurodegenerative disorders affecting forebrain neurons.
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