Nonsense-mediated RNA decay, or NMD, is an evolutionarily conserved molecular mechanism in which potentially defective messenger RNAs, or mRNAs (genetic material that tells the body how to make proteins), are degraded. Disruption of the NMD pathway can cause neurological disorders, immune diseases, cancers and other pathologies. Mutations in human NMD regulators are observed in neurodevelopmental disorders, including autism and intellectual disability.
Why NMD mutations are enriched in neurodevelopmental disorders remains a mystery. Sika Zheng, professor of biomedical sciences in the School of Medicine and founding director of the Center for RNA Biology and Medicine at the University of California, Riverside, led a study published in the journal Neuronwhich reveals the molecular cellular mechanism underlying NMD regulation of brain size and its deregulation by causing microcephaly, a condition in which a baby’s head is much smaller than expected.
The team’s finding suggests that maintaining neuronal NMD function is essential for early brain development to prevent microcephaly. According to Zheng, modulation of NMD targets may be a potential treatment for microcephaly and other 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 regulating mRNA decay and controlling brain size. Furthermore, 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 funded by grants from the National Institutes of Health and the California Institute for Regenerative Medicine. The title of the research paper is “Epstatic 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 City of Hope, Gene Yeo of UC San Diego, and members of her lab.