Title: MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome
Legend: Left: Models for FMRP regulation of the MDM2 and P53 pathway, which impacts adult neurogenesis and cognition. Right upper: Schematic of novel location test for assessing spatial learning. Right lower panel Nutlin-3 treatment fully rescued spatial memory deficits in Fmr1 KO mice in the novel location test (n = 9-13 mice per group). Right lower: Nutlin-3 treatment rescues cognitive functions in Fmr1 KO mice.
Citation: Li Y, Stockton ME, Bhuiyan I, Eisinger BE, Gao Y, Miller JL, Bhattacharyya A, Zhao X. (2016). MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. Science Translational Medicine, 27;8(336):336ra61. doi:10.1126/scitranslmed.aad9370.
Abstract: 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.
About the lab: The research in Zhao laboratory focuses on understanding the molecular mechanisms that regulate neural stem cells and neurodevelopment with the goal of applying this knowledge in the treatment of neurological disorders and injuries. Neurodevelopmental disorders are highly heterogeneous constellation of disorders, both in terms of etiology and clinical manifestations. Using neural stem cells as model systems, the lab is investigating the molecular mechanisms that regulate neuronal development during postnatal period and their implications in human neurodevelopmental disorders such as Rett Syndrome, Autism, and Fragile X syndrome.