New drug hopes for breakthrough for incurable neurodegenerative myelin diseases
Summary: Riluzole, an FDA-approved drug for the treatment of ALS, may, in part, 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 Institute for Clinical Research in Montreal (IRCM) and professor of biochemistry and molecular medicine at the University of Montreal’s Faculty of Medicine.
Published in the magazine 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 has been shown that riluzole can counteract this assembly defect,” said Maxime Pinard, the researcher responsible for the project at Coulombe’s laboratory.
“For diseases that are as serious and debilitating to patients and their families as the leukodystrophies, learning about such advances in knowledge holds 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 the process of demyelination (damage to the myelin sheath) of the central and peripheral nervous system. The process is primitive in appearance and is not 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: “It clearly suggests that Riluzole could be used as a drug to treat this disease.”
About this news about neuropharmacological research
Original Research: Open access.
“Riluzole partially restores RNA polymerase III complex assembly in cells expressing the leukodystrophy variant POLR3B R103H” by Maxime Pinard et al. Molecular Brain
Riluzole partially restores RNA polymerase III complex assembly in cells expressing the leukodystrophy 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-nuclear (sn) RNAs in eukaryotes, is not clearly understood.
The recent discovery of the HSP90 co-chaperone PAQosome revealed the function of this machinery in the biogenesis of nuclear RNA polymerases.
However, the relationship 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 assembly.
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 reveal that riluzole, an FDA-approved drug to alleviate the symptoms of ALS- a, 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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