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Nonsense-mediated RNA decay, or NMD, is an evolutionarily conserved molecular mechanism in which potentially defective messenger RNAs, or mRNAs (genetic material that instructs the body on how to make proteins), are degraded. Disruption of the NMD pathway can lead to neurological disorders, immune diseases, cancers, and other pathologies. Mutations in human NMD regulators are seen in neurodevelopmental disorders, including autism and intellectual disability.
Why NMD mutations are enriched in neurodevelopmental disorders remains a mystery. Sika Zheng, a professor of biomedical sciences in the School of Medicine and the founding director of the Center for RNA Biology and Medicine at the University of California, Riverside, has now led a study, published in the journal Neuron, that reveals the molecular cellular mechanism underlying NMD regulation of brain size and its dysregulation in causing microcephaly — a condition in which a baby’s head is much smaller than expected.
The team’s finding suggests that maintaining the neuronal NMD function is essential for early brain development to prevent microcephaly. According to Zheng, modulating NMD targets can be a potential treatment for microcephaly and other related neurodevelopmental diseases.
The study explains the functional roles of NMD in brain development and the underlying mechanistic action. It also demonstrates for the first time the link between mRNA decay regulation and brain size control. Additionally, it reveals the intricate connection between NMD and the most famous tumor suppressor gene, p53, suggesting possible new connections between NMD and cancer.
The research was supported by grants from the National Institutes of Health and the California Institute of Regenerative Medicine. The title of the research paper is “Epistatic Interactions between NMD and TRP53 Control Progenitor Cell Maintenance and Brain Size.” Zheng was joined in the study by Liang Chen of the University of Southern California, Chun-Wei Chen of the City of Hope, Gene Yeo of UC San Diego, and members of their labs.