In their present work, Wilkinson and colleagues report the discovery that human cells have evolved a way to overcome attacks on the NMD pathway. If any molecule of the pathway is injured, the cell sends reinforcement molecules to compensate for the loss.
"These reinforcements are not sent out from all cells of our body but only selectively in certain cells; in some cases they appear to be sent from cells that need reinforcements the most," Wilkinson said.
"This is an important feature of this compensatory ("buffering") response that could potentially be relevant for clinical application," Wilkinson said. "To appreciate this, one first needs to realize that a very large proportion of people with genetic diseasesone-third, in facthave a faulty gene with a mutation that leads to an early stop signal. As a consequence, most of these genes will give rise to an mRNA that is degraded by NMD and hence the encoded protein is never made. A key point is that a proportion of these mutant proteinsalthough shorter than normalis actually still functional. So, if clinicians could inhibit NMD, this would potentially ameliorate the symptoms of some of these diseases because this treatment would increase the production of these short, but still functional, proteins."
"Unfortunately, a global NMD blockade would also lead to the production of lots of other short proteins, some of which would be toxic," Wilkinson noted. As a result, "in the past, there has been little interest in 'NMD-inhibition therapy.'" The new discovery makes NMD-inhibition therapy much more attractive because the tissue-specific compensatory response has the potential to greatly dampen the side effects. "By choosing a branch of the NMD pathway that is subject to compensa
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University of California - San Diego