Research News

Researchers at Cleveland Clinic found that the enzyme Dicer1 affects remyelination and demyelination processes in multiple sclerosis (MS) through its role in producing small molecules called microRNAs.

MicroRNAs (miRNA) are small pieces of RNA in the cell nucleus that control gene regulation. miRNA are a newer research interest area; they were discovered in the early 1990s by two scientists who won the 2024 Nobel Prize in Physiology or Medicine for their work. miRNAs are processed by the enzyme Dicer1 to perform their biological function. The Cleveland Clinic study, published in Neurobiology of Disease and led by Ranjan Dutta, PhD, is the first to map out how the Dicer1 enzyme and miRNAs regulate microglial function in progressive MS.

“There had been research in the past that shed light on the function of microglial cells associated with MS, but we didn’t know that miRNAs are an integral part to control the function of microglia,” Dr. Dutta explains. “Our findings were the first to show that when miRNAs are not processed in microglial cells, they lose their ability to conduct critical functions, including repair.”

During MS, microglia — immune cells present in the brain itself, lining the edge of demyelinated areas — become highly active. Conventional wisdom long held that microglia only served a destructive role in MS until a study authored by Dr. Dutta along with Bruce Trapp, PhD showed microglia’s effects are more nuanced and may help slow down damage, depending upon where in the brain they’re located.

Dr. Dutta’s lab focuses on progressive MS, when remyelination slows down or stops completely.

“We’re trying to ask what, apart from age, is happening to the brain that causes the cells that were conducting repair to stop doing so?” Dr. Dutta says. “To answer this, we conduct our studies in a unique way, by taking our observations in MS patient brain samples and then further investigating the mechanisms in preclinical models.”

Dr. Dutta first observed that the Dicer1 enzyme was expressed in microglial cells in MS lesions through examining samples from Cleveland Clinic’s MS rapid autopsy program. To map out exactly what microglial miRNAs do, the team recreated this condition in preclinical models with the deletion of the miRNA processing enzyme Dicer1 in microglial cells. Preclinical experiments showed that without Dicer1, inflammation-related signals were turned up, while genes that normally help keep microglia in a healthy state were turned down. The cascading effects led to microglia continuously releasing inflammation signals, leading to more widespread demyelination and preventing remyelination. 

Dr. Dutta says considering miRNAs are needed for the critical functioning of cells, Dicer1 could be a promising target for drug development. The MS research field is lacking biomarkers that can be indicative of disease progression and drug response, and Dr. Dutta’s lab also plans to study the presence of miRNAs as potential biomarkers in the cerebrospinal fluid that surrounds and protects the brain and spinal cord. Identification of miRNAs associated with the disease process in MS patients would be a major advancement in the field of MS research.