A new drug breakthrough that offers hope for incurable neurodegenerative myelin diseases

Abstract: Riluzole, an FDA-approved drug for the treatment of ALS, may partially correct the molecular cause of some leukodystrophies.

Source: University of Montreal

There is new hope for the future treatment of some leukodystrophies, neurodegenerative diseases in young children that progressively affect their quality of life, often leading to death before adulthood.

The development stems from the work of Benoit Coulombe, director of the Translational Proteomics Laboratory at the Montreal Clinical Research Institute (IRCM) and professor of biochemistry and molecular medicine at the University of Montreal’s Faculty of Medicine.

Published in the magazine The molecular brainnew research shows that the drug Riluzole, approved by the US Food and Drug Administration to treat certain forms of amyotrophic lateral sclerosis, can at least partially correct the molecular cause of some leukodystrophies.

“Indeed, we have shown that the causative mutations of some leukodystrophies affect the subunits of an important cellular enzyme, RNA polymerase III, preventing its normal assembly – it turns out that Riluzole can prevent this assembly error,” said Maxime Pinard, the responsible researcher for the project in the Coulombe laboratory .

“For diseases as serious and debilitating for patients and their families as the leukodystrophies, learning about such advances in knowledge carries a great deal of hope, which the IRCM warmly welcomes,” added Dr. Jean-François Côté, President and Scientific Director of the IRCM .

Leukodystrophies are rare and almost exclusively genetic diseases characterized by the process of demyelination (damage to the myelin sheath) of the central and peripheral nervous system. The process is primitive in appearance and non-inflammatory and leads to cerebral sclerosis.

“More work is needed to evaluate the effect of Riluzole on patients to advance the development of therapeutic pathways for these diseases,” warned Marjolaine Verville, co-founder of the Leukodystrophy Foundation.

But already, she added, “the research from Dr. Coulombe’s lab is generating a lot of interest and hope in the community.” Her husband and co-founder of the Foundation, Éric Tailleur, agreed: “This clearly suggests that Riluzole could be used as a drug to treat this disease.”

About this neuropharmacology research news

Author: Press office
Source: University of Montreal
Contact: Press Office – University of Montreal
Picture: The image is in the public domain

Original research: Open access.
“Riluzole partially restores RNA polymerase III complex assembly in cells expressing the leukodystrophy-causing variant POLR3B R103H” by Maxime Pinard et al. The molecular brain

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Abstract

Riluzole partially restores RNA polymerase III complex assembly in cells expressing the leukodystrophy-causing variant POLR3B R103H

The assembly mechanism of RNA polymerase III (Pol III), a 17-subunit enzyme that synthesizes tRNA, 5 S rRNA, and other small core (sn) RNAs in eukaryotes, is not clearly understood.

The recent discovery of the HSP90 co-chaperone PAQosome (quaternary structure ordering particle) revealed the function of this machinery in the biogenesis of nuclear RNA polymerases.

However, the connection between Pol III subunits and the PAQosome during the assembly process remains unexplored. Here we report the development of a mass spectrometry-based assay that enables the characterization of Pol III composition.

This assay was used to dissect the stages of Pol III assembly, to begin to define the function of the PAQosome in this process, to dissect the assembly defects caused by the leukodystrophy-causing R103H substitution in POLR3B, and to discover that riluzole, an FDA-approved drug to alleviate the symptoms of ALS, it partially corrects those shortcomings of the assembly.

Together, these results shed new light on the mechanism and regulation of human Pol III nuclear biogenesis.