In vitro and in vivo characterization of the RE-1 Silencing Transcription Factor (REST) activity under neuroinflammatory conditions

The ability to specifically target epigenetic and molecular mechanisms involved in neuronal development could be an alternative therapeutic strategy for neuroinflammatory/neurodegenerative disorders such as Multiple Sclerosis (MS). The transcriptional repressor RE1-Silencing Transcription Factor (REST) regulates neurogenesis and neuronal identity through cell-specific gene repression, allowing expression of its targets in mature neurons where REST is quiescent. REST dysregulation has been implicated in several neurodegenerative disorders, including Alzheimer and Huntington diseases, tumors of the nervous system, and epilepsy. We found that REST is overexpressed in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), suggesting that its dysregulation might be an important factor in the pathogenesis of the disease. Starting from these observations, we have firstly analyzed the expression of REST target genes in EAE and characterized the cell-specificity of REST overexpression, investigating the differential contribution of neuronal and glial cell populations to REST upregulation. Moreover, in order to mimic the inflammatory EAE scenario, we have analyzed REST activity in primary neuron cultures treated with various pro-inflammatory cytokines. Altogether, this study provides the basis for understanding the molecular mechanisms of REST expression during brain inflammation and its implication in the subsequent neurodegenerative processes.