Study Investigates Protein Receptor Subtype for Promoting Remyelination in MS

Multiple sclerosis (MS) involves the progressive loss of the protective layer of nerve fibers, myelin, and its loss, called demyelination, results in symptoms of MS. Blocking the protein receptor, muscarinic type 3 (M₃R), may be effective in promoting remyelination in patients with MS, based on the results of a study published by the Journal of Neuroscience.

Triggering remyelination results in the formation of new myelin sheaths and plays a significant role when developing effective MS treatments. The process of remyelination is spontaneous, but involves the transformation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes.

Previous research has demonstrated that muscarinic receptors (MR) can bind the neurotransmitter acetylcholine, and can induce the differentiation of OPCs, and, therefore, speed remyelination.

“The identification of drug targets aimed at improving remyelination in patients with demyelination disease is a key step in development of effective regenerative therapies to treat diseases such as multiple sclerosis,” the authors wrote. “Muscarinic receptor antagonists have been identified as effective potentiators of remyelination but the receptor subtypes that mediate these receptors are unclear.”

Despite the limited research of MRs in the clinical setting, the study aimed to assess the ability of MRs in promoting remyelination for patients with MS. Specifically, the researchers hypothesized that M₃Rs may be the functionally relevant MR subtype in remyelination.

The study results revealed that genetically manipulating in the lab human OPCs to decrease the among of M₃R augmented the cells’ differentiation in oligodendrocytes. The results also showed that transferring OPCs with lower M₃R levels to mice with myelin deficits had improved remyelination. Furthermore, selective removal of M₃Rs from adult OPCs increased their differentiation and, therefore, led to improved remyelination in the mice.

“This work establishes that M₃R has a functional role and, if blocked, could improve myelin repair,” Fraser J. Sim, PhD, the study’s senior author, said in statement. “It better positions the field for clinical trials that will be aimed at blocking these receptors in MS patients.”

The researchers recently received $1.7 million in funding from the National Institutes of Health to continue their research on the role of M₃R in remyelination and to assess its efficacy as a therapeutic target.

“The hope is that this will identify new and more attractive drug targets beyond M3R,” Sim concluded. “The grant also is geared toward understanding how the receptors are activated in disease. If we can understand that, then we might have another opportunity for targeting this pathway in MS.”

Reference

Welliver RR, Polanco JJ, Seidman RA, et al. Muscarinic receptor M₃R signaling prevents efficient remyelination by human and mouse oligodendrocyte progenitor cells. [published online June 29, 2018]. J Neurosci. doi: 10.1523/JNEUROSCI.1862-17.2018.