期刊
NEURON
卷 104, 期 4, 页码 665-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2019.08.027
关键词
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资金
- NIH [NIMH 096816, NINDS 076708, HL007676]
- Sammons Enterprises
- Intellectual Disability Research Center [P30HD024064]
- IDDRC Neuropathology Core (NICHD) [U54HD083092]
- BCM Cytometry and Cell Sorting Core [RR024574, AI036211, CA125123]
- Novo Nordisk Foundation
- Australian State of Victoria Government Operational Infrastructure Support Program
- Australian National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme (IRIISS)
- Australian NHMRC [1155224, 1091593]
- Australian Research Council [DE160100620]
- NHMRC Centre of Research Excellence [1116976]
- NHMRC practitioner fellowship [1105008]
- career development fellowship [1063799]
- practitioner fellowship [1006110]
- senior research fellowship [1102971]
- [1127144]
- National Health and Medical Research Council of Australia [1091593, 1155224] Funding Source: NHMRC
- Australian Research Council [DE160100620] Funding Source: Australian Research Council
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-Frameshift 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.
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