Blocking Protein Receptor Called M3R Seen to Promote Remyelination in Mice Model, Study Reports

Jose Marques Lopes, PhD avatar

by Jose Marques Lopes, PhD |

Share this article:

Share article via email
remyelination Convelo Genentech collaboration

Blocking a protein receptor called muscarinic type 3 (M3R) could be an effective way to promote remyelination in multiple sclerosis (MS) patients, according to a State University of New York at Buffalo (UB) study in mice.

The research, “Muscarinic receptor M3R signaling prevents efficient remyelination by human and mouse oligodendrocyte progenitor cells,” was published in the Journal of Neuroscience.

MS is characterized by the progressive loss of the protective layer of nerve fibers, called myelin, that is essential for effective transmission of nerve impulses. Its loss, called demyelination, leads to MS symptoms. As a result, understanding how to trigger remyelination, the formation of new myelin sheaths, is regarded as key for more effective MS treatments.

Remyelination spontaneously occurs in MS lesions, but becomes increasingly incomplete and eventually fails. The process involves the transformation — or differentiation — of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes, which ultimately produce myelin.

Muscarinic receptors (MRs) are one of two types of receptors that bind the neurotransmitter acetylcholine. Research has shown that MR blockers induce the differentiation of OPCs and speed remyelination. However, their use in the clinical setting has been precluded by the lack of information on what receptor subtype is involved.

M3R receptors control processes such as muscle contraction, sweating, food intake, and body weight. As they are plentiful on OPCs, scientists hypothesized that M3Rs may be the functionally relevant MR subtype in remyelination.

The UB team found that genetically manipulating in the lab (in vitro) human OPCs so as to reduce the amount of M3R augmented the cells’ differentiation into oligodendrocytes. The investigators also demonstrated that transferring OPCs with lower M3R levels to mice with myelin deficits improved remyelination. Selective removal of M3Rs from adult OPCs also boosted their differentiation and resulted in better remyelination in the mice.

Overall, the findings show that M3R in oligodendrocyte progenitor cells “act to delay differentiation and remyelination, suggesting that M3 receptors are viable targets for human demyelinating disease,” the researchers wrote.

“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 a UB news release, written by Ellen Goldbaum. “It better positions the field for clinical trials that will be aimed at blocking these receptors in MS patients.”

The findings build on prior work by Sim’s team, which showed that M3R activation blocks oligodendrocyte differentiation in both humans and rodents. The team also demonstrated that solifenacin, a medication available as VESIcare (marketed by Astellas Pharma) and approved to treat overactive bladder, blocked M3Rs and promoted remyelination in an animal model.

“That work identified solifenacin as a possible drug useful for remyelination, but we really weren’t sure which specific receptor the drug worked on,” Sim said. Lack of specificity for a single receptor type could induce unwanted side effects in patients, he added.

The research team recently was awarded $1.7 million in funding from the National Institutes of Health (NIH) to further investigate the role of M3R in remyelination and to evaluate its potential as a therapeutic target.

“The hope is that this will identify new and more attractive drug targets beyond M3R,” Sim said. “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.”

MS Podcast
MS sidelined his dreams of playing pro football, so Tyler called an audible! Listen in as Jenn chats with Tyler Campbell, son of Football Hall of Fame legend Earl Campbell.

Listen here.

Dancing Doodle

Did you know some of the news and columns on Multiple Sclerosis News Today are recorded and available for listening on SoundCloud? These audio news stories give our readers an alternative option for accessing information important for them.

Listen Here