Research ArticleFragile X Syndrome

MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome

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Science Translational Medicine  27 Apr 2016:
Vol. 8, Issue 336, pp. 336ra61
DOI: 10.1126/scitranslmed.aad9370

MDM2 inhibitor rescues fragile X deficits

Mutation of the FMRP protein in humans leads to fragile X syndrome, the most common inherited intellectual disability. Li et al. now show that FMRP controls the activities of neural stem cells in the adult mouse brain, which is critical for production of new neurons and learning and cognition. They discovered that FMRP regulates neural stem cells through controlling the expression of the E3 ubiquitin ligase MDM2. They found that treatment with an inhibitor of MDM2 called Nutlin-3 rebalanced neural stem cell activities and rescued cognitive deficits in a mouse model of fragile X syndrome.


Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome.

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