Weakened cerebellum could explain onset of motor disorders: Montreal study

A fragile cerebellum at birth could explain the onset of motor disorders several decades later, according to research conducted by a Montreal team.

A team from the Centre de recherches du Centre hospitalier de l’Université de Montréal, known as CRCHUM, led by Éric Samarut and Fanny Nobilleau, has found that the RFC1 gene, best known for its role in DNA repair, actually plays a key role in the formation of the cerebellum, the area of the brain that coordinates our movements.

“We do functional neurogenetics, so we’re interested in the function of genes involved in diseases, and in particular, we’re interested in rare neurological diseases,” explained Professor Samarut. “What we’re trying to do is understand what these genes do when everything is working properly, to better understand how mutations in these genes can cause disease.”

The absence of the RFC1 gene leads to early cerebellar malformations, paving the way for the possible onset of disorders such as CANVAS syndrome (cerebellar ataxia, neuropathy, vestibular areflexia syndrome), a rare disease for which there is currently no treatment.

During embryo development, Samarut explained, researchers were “somewhat surprised” to find that the RFC1 gene is mainly expressed in the cerebellum.

By studying brain development in zebrafish models, the CRCHUM team discovered that the absence of RFC1 leads to the death of cells that would have developed into neurons, creating a malformation of the cerebellum in the early stages of life, according to a press release.

During the development of the cerebellum in the embryo, said Samarut, the RFC1 gene acts as a “guardian of genome integrity, ensuring that the genome is well maintained and managed throughout development and neuron production.”

“And when RFC1 is not there, the whole system pauses and these cells that should become neurons end up dying or committing suicide,” he said.

Researchers are therefore wondering whether a disruption of RFC1 could weaken the cerebellum and possibly lead to the development of motor disorders several decades later.

“Usually, genetic causes are mutations in genes, so that’s going to impact the normal functioning of the gene,” said Samarut. “Here, it’s a little more complicated: these are repeated expansions, so portions of DNA that are repeated in abnormal amounts. But we don’t know at all how these repeated expansions are going to cause the problem.”

In this case, he continued, “We don’t know what’s going on at all, we only know that these expansions are found near a gene called RFC1.” Researchers do not understand, for example, whether RFC1 is defective from the time the cerebellum is formed or whether it malfunctions later.

Researchers are now trying to determine whether RFC1 activity is defective in people with CANVAS and whether it is responsible for the resulting motor difficulties.

Although clinical applications are still a long way off, the study reveals previously unknown mechanisms, paving the way for research, particularly into neurodegenerative diseases such as atypical Parkinson’s syndromes and multiple system atrophy, according to the researchers.

If researchers can demonstrate that impaired RFC1 function is the cause of the disease, said Samarut, it will help clarify the form that potential treatments might take. It would also mean that patients who develop symptoms in their 50s or 60s have structural defects in their cerebellum long before the first signs of the disease appear.

“It would mean that we could diagnose the disease and possibly intervene before the first symptoms appear, and that could be a game changer for patients,” concluded Samarut.

The findings of this study were published in the journal Nature Communications.

–This report by La Presse Canadienne was translated by CityNews