Summary: Riluzole, an FDA-approved drug to treat ALS, can, in part, correct the molecular cause of some leukodystrophies.
Source: University of Montreal
There’s 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 Clinical Research Institute of Montreal (IRCM) and a professor of biochemistry and molecular medicine in the Faculty of Medicine of Université de Montréal.
Published in the journal Molecular Brain, the new research shows that the drug Riluzole, approved by the U.S. 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 turned out that Riluzole can counteract this assembly defect,” said Maxime Pinard, the researcher responsible 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 carries a great deal of hope, which IRCM warmly welcomes,” added Dr. Jean-François Côté, the IRCM’s president and scientific director.
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.
“More work is needed to evaluate the effect of Riluzole on patients in order to advance the development of therapeutic avenues for these diseases,” cautioned Marjolaine Verville, co-founder of the Leukodystrophy Foundation.
But already, she added, “the research from Dr. Coulombe’s laboratory is generating a lot of interest and hope in the community.” Her husband and Foundation co-founder, Éric Tailleur, agreed: “It clearly suggests that Riluzole could be used as a drug to treat this disease.”
Riluzole partially restores RNA polymerase III complex assembly in cells expressing the leukodystrophy-causative variant POLR3B R103H
The mechanism of assembly of RNA polymerase III (Pol III), the 17-subunit enzyme that synthesizes tRNAs, 5 S rRNA, and other small-nuclear (sn) RNAs in eukaryotes, is not clearly understood.
The recent discovery of the HSP90 co-chaperone PAQosome (Particle for Arrangement of Quaternary structure) revealed a function for 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 was used to dissect the stages of Pol III assembly, to start defining the function of the PAQosome in this process, to dissect the assembly defects driven by the leukodystrophy-causative R103H substitution in POLR3B, and to discover that riluzole, an FDA-approved drug for alleviation of ALS symptoms, partly corrects these assembly defects.
Together, these results shed new light on the mechanism and regulation of human nuclear Pol III biogenesis.