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.
