Repurposing Drugs to Dampen Hyperactive Nonsense-Mediated Decay in Fragile X Syndrome

With a $90,000 grant from the FRAXA Research Foundation, Dr. Lynne Maquat and Dr. Tatsuaki Kurosaki will investigate nonsense-mediated mRNA decay (NMD) in Fragile X. NMD is a “housekeeping” process that cells use to prevent faulty proteins from being made. But there is too much of it in Fragile X syndrome. There are already available drugs that suppress NMD – including caffeine — and so if this project is successful, it could lead to new off-the-shelf Fragile X treatments.

$90,000 Grant
Tatsuaki Kurosaki, PhD
FRAXA Postdoctoral Fellow
Lynne Maquat, PhD
Principal Investigator
University of Rochester
2015-2016 FRAXA Research Grant
$90,000 over 2 Years

Fragile X syndrome is the result of abnormally large expansions in the Fragile X gene that silence gene expression. When silenced, cells fail to produce a protein, FMRP, which is critical for our neurons to function properly.

At the molecular level, FMRP represses the production of other proteins that mediate neuronal maturation and synaptic plasticity either directly or indirectly.

We have serendipitously found that a cellular RNA destruction mechanism studied in our laboratory, called nonsense-mediated mRNA decay (NMD), is hyperactive in Fragile X syndrome, providing new insight into the cause of this disease. There are already drugs on the market that have been shown to inhibit NMD — including caffeine — and that we propose can be re-purposed for this outcome. We expect our studies will provide a more complete understanding of the cellular abnormalities that cause Fragile X syndrome so as to aid in the development of previously unforeseen and efficacious therapeutic strategies.

Further Reading: Research Articles

Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression

Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense p53 mutations

Explore Current Fragile X Research

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