Summary: Riluzole, an FDA-approved drug to treat ALS, may, in part, correct the molecular cause of some leukodystrophies.
Source: Montreal university
There is new hope for the future treatment of certain 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 Faculty of Medicine of the University of Montreal.
Published in the journal molecular brainthe new 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 certain leukodystrophies.
“Indeed, we have shown that the causative mutations of certain leukodystrophies affect the subunits of an important cellular enzyme, RNA polymerase III, preventing its normal assembly – it turned out that Riluzole can counteract this defect of ‘assembly,’ said Maxime Pinard, the lead researcher for the project in Coulombe’s lab.
“For diseases as serious and debilitating for patients and their families as leukodystrophies, learning about such advances in knowledge brings great 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 a 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.
“Additional work is needed to assess the effect of Riluzole on patients in order to advance the development of therapeutic avenues for these diseases,” warned Marjolaine Verville, co-founder of the Leukodystrophy Foundation.
But already, she adds, “the research from Dr. Coulombe’s laboratory is generating a lot of interest and hope in the community”. Her husband and co-founder of the Foundation, Éric Tailleur, confirmed: “This clearly suggests that Riluzole could be used as a medicine to treat this disease.”
About this neuropharmacology research news
Author: Press office
Source: Montreal university
Contact: Press service – University of Montreal
Image: Image is in public domain
Original research: Free access.
“Riluzole partially restores RNA polymerase III complex assembly in cells expressing the leukodystrophy-causing variant POLR3B R103H” by Maxime Pinard et al. molecular brain
Riluzole partially restores RNA polymerase III complex assembly in cells expressing leukodystrophy-causing variant POLR3B R103H
The assembly mechanism of RNA polymerase III (Pol III), the 17-subunit enzyme that synthesizes tRNAs, 5S rRNA, and other small-nucleus (sn) RNAs in eukaryotes, does not is not clearly understood.
The recent discovery of the co-chaperone HSP90 PAQosome (Particle for Arrangement of Quaternary structure) revealed a 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 allows the characterization of Pol III assembly.
This assay has been used to dissect the steps of Pol III assembly, to begin to define the function of the PAQosome in this process, to dissect assembly defects driven by the R103H substitution responsible for leukodystrophy in POLR3B, and to uncover that riluzole, an FDA-approved drug for ALS symptom relief, partially corrects these assembly defects.
Together, these results shed new light on the mechanism and regulation of human nuclear Pol III biogenesis.
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