In zebrafish, researchers at the CRCHUM discover that the RFC1 gene plays a key role in the development of the brain region that coordinates movement.

Could an anomaly in the developing brain explain motor difficulties occurring decades later in people with rare movement disorders?

These are the genetics being investigated by researchers at Université de Montréal’s affiliated hospital research centre, the CRCHUM, led by scientist Éric Samarut and PhD candidate Fanny Nobilleau.

They describe their progress in a study published in July in Nature Communications.

In their research, the scientists discovered that the RFC1 gene plays a key role in the formation of the cerebellum, a region of the brain that coordinates movement.

This discovery opens up new avenues for understanding the biological origins of late-onset cerebellar ataxias. These are rare disorders characterized by difficulties with motor coordination.

The prevalence of this large family of disorders is estimated to impact 1 to 3 out of every 100,000 people. To date, they are untreatable.

A universal gene with an unexpected role

For a long time, RFC1 has been viewed as a simple DNA mechanic, tasked with fixing errors that occur during cellular multiplication.

“We thought that this universal gene acted everywhere, throughout the body, like a quality controller ensuring DNA integrity,” said Samarut, an assistant professor at UdeM. “But during embryonic development, we were surprised to see that it is expressed above all in the cerebellum.”

By studying the developing brain in zebrafish models, the team at CRCHUM found that the absence of RFC1 causes cells that would have developed into neurons to die, resulting in cerebellum malformations from the earliest stages of life.

“This is the first time that a research team has studied the function of this gene in an in vivo model,” said Samarut. “This step is essential before extrapolating our discoveries to the context of these disorders.”

Rare disorders but fundamental questions

This discovery shines a light on potential biological mechanisms behind some late-onset cerebellar ataxias, like CANVAS (Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome).

This rare disorder, often without a genetic diagnosis, has been linked to gene expansions within the RFC1 gene. These expansions occur when the cellular machinery responsible for copying DNA makes an error and adds extra nucleotides in a gene.

It is still unknown how these anomalies can affect the brain and cause specific motor difficulties. However, the recent advances made by Samarut’s team suggest that RFC1’s normal functions may be altered with this syndrome.

“What we’re seeing right now is that the absence of RFC1 prevents cerebellum cells from properly developing,” says Samarut.

“Could such a cerebellum, fragile from birth, lead to motor difficulties much later in life? That’s still to be determined. If this line of thinking was proven, it would clear the way for earlier diagnosis, even before symptoms become manifest.”

Samarut’s team is now working to determine whether RFC1 activity is defective in people with CANVAS and whether it is responsible for the resulting motor difficulties.

A promising starting point

Done in collaboration with Nicolas Pilon, who specializes in the genetics of rare conditions at Université du Québec à Montréal, this research is funded by $330,000 in grants that Samarut and his CRCHUM colleague Martine Tétreault, received in 2024 to study late-onset cerebellar ataxia.

Their project was one of three winners of the Innovative Therapies for Hereditary Ataxias competition funded by Génome Québec, Ataxia Canada and Muscular Dystrophy Canada.

While any clinical applications are still a long way away, their study has revealed previously unknown mechanisms, defining the way forward for research, especially for neurodegenerative diseases like atypical parkinsonian syndromes and multiple system atrophy. 
 

Author: Bruno Geoffroy