NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease

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.

Are painDETECT scores in musculoskeletal disorders associated with duration of daily pain and time elapsed since current pain onset?

“…Further studies mixing various musculoskeletal conditions could longitudinally assess both painDETECT (and/or DN4) scores and daily pain duration (eg, using a diary to assess it prospectively), early after the onset of a new pain episode to reproduce, or not, these findings. Similar observations would suggest that high painDETECT scores do not require lasting anatomical lesions in peripheral nerves or the central nervous system but may rather result from early epigenetic changes 37,40 and/or genetically encoded traits, leading to more rapid sensitization of neurons or glial cells. Genetic traits indeed appeared to be nearly as important as environmental or traumatic influences for high painDETECT scores in a recent large epidemiological study of 4324 people and 1357 twins, which concluded that, as for chronic widespread pain, high painDETECT scores were best explained by a combination of similar heritable traits, accounting for 37% (95% CI: 23%–50%) of the variance, and unique environmental factors, accounting for 63% (95% CI: 49%–79%).…”

“…Indeed, functional and very early changes in peripheral nerves or the central nervous system (ie, more neuroplastic than neuropathic, such as epigenetic changes in neurons and/or glial cells) could account more for the painDETECT scores than the sprouting of new nerves or anatomical lesions (such as those induced in entrapment neuropathies by chronic nerve compression or ischemia). For example, dysregulation of transcriptional repressors, such as neuron restrictive silencer factor, contributes to neuropathic pain through epigenetic mechanisms 37 and repression (by neuron restrictive silencer factor) of Nav1.8, leading to hypoesthesia and the repression of mu-opioid receptor genes, resulting in the loss of endorphins and morphine analgesia. 39…”

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

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Transcription factors are potential therapeutic targets in epilepsy

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