The REST/NRSF pathway as a central mechanism in CNS dysfunction

Abstract

Deciphering the complex molecular circuitry of the brain is crucial for understanding how processes such as higher cognitive function and behaviour are disrupted in neurological disease. Thus it is imperative to explore further the regulatory mechanisms centred on key transcription factors that orchestrate such processes including REST/NRSF (restrictive element-1 silencing transcription factor/neuron restrictive silencing factor); NRSF targets over 2,000 human genes and plays a central and dynamic role in a myriad of CNS processes. To address the function of NRSF, I employed several research disciplines including bioinformatics, gene association studies for complex polygenic diseases and model systems for understanding the structure and function of several NRSF directed pathways in the CNS. My data demonstrated that disruption of the normal balance of NRSF within the cell may be a fundamental mechanism across a range of common neuropathologies. These included 1) schizophrenia, where NRSF was shown to be capable of directing allele-specific and stimulus-driven expression of MIR137 through identification of a novel promoter in this key schizophrenia genome wide associated gene; 2) cognitive dysfunction, polymorphisms within NRSF and its gene target BDNF influenced memory performance in patients with newly diagnosed epilepsy; 3) mood disorders, NRSF-signalling was identified as a significant pathway regulating cellular processes relevant to mood modification by pharmaceutical challenge and 4) NRSF-mediated regulation of microRNA-137 (miR-137) expression was demonstrated in vivo using a model of cortical spreading depression, consistent with its involvement in associated neuropathologies including epilepsy and ischemia. The analysis was expanded to a common non-neurological disease, breast cancer, where the previous work of others was extended to demonstrate a link between NRSF and miR-137 through the novel promoter identified in this study. Collectively these findings emphasise NRSF as a major contributor to cell pathogenesis, in part by modulation of miR-137, not only in a neuronal context but also in other systems