Abstract
The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural precursor cells to adult neurons has been well characterized in stem cell models. While much has been characterized from a developmental perspective, research is revealing that NRSF plays a role in various neurological diseases, ranging from neurodegenerative, neuropsychiatric, to cancer. Dysregulation of NRSF activity disrupts downstream gene expression that is responsible for neuronal cell homeostasis in several models that contribute to pathologic states. Interestingly, it is now becoming apparent that the dysregulation of NRSF contributes to neurological disease through epigenetic mechanisms. Although NRSF itself is a transcription factor, its major effectors are chromatin modifiers. At the level of epigenetics, changes in NRSF activity have been well characterized in models of neuropathic pain and epilepsy. Better understanding of the epigenetic basis of brain diseases has led to design and use of small molecules that can prevent NRSF from repressing gene expression by neutralizing its interactions with its chromatin remodelers. This review will address the basic function of NRSF and its cofactors, investigate their mechanisms, then explore how their dysfunction can cause disease states. This review will also address research on NRSF as a therapeutic target and delve into new therapeutic strategies that focus on disrupting NRSF’s ability to recruit chromatin remodelers.
Highlights
The first indication of the existence of a neural repressor came from study of the sodium voltage-gated channel alpha subunit 2 gene (SCN2A) and a neuron-specific marker, superior cervical ganglion-10 (SCG10) [1,2]
The characterization of the promoter regions showed that a 21-bp neural restrictive silencer element (NRSE) was responsible for gene repression and it was bound by nuclear extracts from non-neural tissue, but not neural tissue
Upregulation of Neuron Restrictive Silencer Factor (NRSF) in response to brain insults, such as ischaemia [18], is believed to be neuroprotective [19] in the short term, but may leave long term epigenetic changes that underlie neuropathic pain, epilepsy, and contribute to neurodegeneration. As these molecular mechanisms begin to be resolved, it is becoming apparent that the use of epigenetic inhibitors to target NRSF and its effector chromatin modifiers opens up the possibility for new therapeutics
Summary
The first indication of the existence of a neural repressor came from study of the sodium voltage-gated channel alpha subunit 2 gene (SCN2A) and a neuron-specific marker, superior cervical ganglion-10 (SCG10) [1,2]. The characterization of the promoter regions showed that a 21-bp neural restrictive silencer element (NRSE) was responsible for gene repression and it was bound by nuclear extracts from non-neural tissue, but not neural tissue This led to the hypothesis that NRSE binding proteins existed and they were important for the differential expression of neural genes between neurons and non-neural cells. During the early development of the nervous system, the downregulation of NRSF de-represses gene neural expression long enough to allow for neurons to differentiate [11]. Upregulation of NRSF in response to brain insults, such as ischaemia [18], is believed to be neuroprotective [19] in the short term, but may leave long term epigenetic changes that underlie neuropathic pain, epilepsy, and contribute to neurodegeneration. As these molecular mechanisms begin to be resolved, it is becoming apparent that the use of epigenetic inhibitors to target NRSF and its effector chromatin modifiers opens up the possibility for new therapeutics
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