Nuclear hormone receptors in demyelinating diseases

Abstract

Demyelination results from the pathological loss of myelin and is a hallmark of many neurodegenerative diseases. Despite the prevalence of demyelinating diseases, there are no disease modifying therapies that prevent the loss of myelin or promote remyelination. This review aims to summarize studies in the field that highlight the importance of nuclear hormone receptors in the promotion and maintenance of myelination and the relevance of nuclear hormone receptors as potential therapeutic targets for demyelinating diseases.These nuclear hormone receptors include the estrogen receptor, progesterone receptor, androgen receptor, vitamin D receptor, thyroid hormone receptor, peroxisome proliferator-activated receptor, liver X receptor, and retinoid X receptor. Pre-clinical studies in well-established animal models of demyelination have shown a prominent role of these nuclear hormone receptors in myelination through their promotion of oligodendrocyte maturation and development. The activation of the nuclear hormone receptors by their ligands also promotes the synthesis of myelin proteins and lipids in mouse models of demyelination. There are limited clinical studies that focus on how the activation of these nuclear hormone receptors could alleviate demyelination in patients with diseases such as multiple sclerosis (MS). However, the completed clinical trials have reported improved clinical outcome in MS patients treated with the ligands of some of these nuclear hormone receptors. Together, the positive results from both clinical and pre-clinical studies point to nuclear hormone receptors as promising therapeutic targets to counter demyelination.

Sexual dimorphism of early transcriptional reprogramming in degenerating peripheral nerves

“…The thyroid hormones (T4 and T3) play an essential role in peripheral nerve regeneration producing a lasting and stimulatory action on axotomized neurons and Schwann cells ( Barakat-Walter, 1999 ). Limited data exist on their role in the development of demyelinating diseases (reviewed in Zorrilla Veloz et al, 2022 ). Disorders of thyroid metabolism are possible causes of inflammation and autoimmune reactions.…”

LXR agonism for CNS diseases: promises and challenges

“…As cholesterol efflux regulatory proteins, several members of ABC transporters including ABCA1, ABCG1/4/5/8 are transcriptionally regulated by LXRs [ 15 ]; these membrane transporters open the gate and translocate sterols outside of cells through conformational change after substrates bind and ATP drives the process [ 17 ]. Next, the combination with ApoE, the dominant apolipoprotein in brain controlled by LXRs, is necessary for the removal from or recycling in the CNS of the effluxed cholesterol [ 18 ]. Based on this ability to regulate multiple genes, LXRs localize in the nexus of cholesterol trafficking in the CNS, and its dysregulation thus leads to various neurodegenerative pathologies.…”

Zebrafish as an emerging model to study estrogen receptors in neural development

“…Estrogen receptors are expressed in both OPCs and oligodendrocytes (OLs), in vitro and in vivo , suggesting that estrogen signaling may play a role in regulating the proliferation, differentiation, and survival of these cells. Indeed, studies have shown that estrogen treatment can increase the number of oligodendrocytes and myelin production, in vitro and in vivo ( 90 ). In particular, estrogen receptors have been shown to play a role in promoting the differentiation of OPCs into mature oligodendrocytes.…”