Highlights
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Humans carrying novel variants in UPF2 exhibit speech and language deficits
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Upf2-deficient mice and flies have impaired NMD and exhibit behavioral deficits
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Inhibition of Upf2-dependent NMD triggers immune activation in mice
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Reduction of brain inflammation reverses synaptic and behavioral deficits
Summary
In humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding
UPF2 (
UP- F rameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking
Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired
UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.
