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

Abstract

Fragile X syndrome, the most common form of inherited intellectual disability, is caused most often by a lack of fragile X mental retardation protein (FMRP). However, the mechanism remains unclear and effective treatment is lacking. Here we show that a loss of FMRP leads to activation of adult neural stem cells (NSCs) and a subsequent reduction in neuronal production. We identified ubiquitin ligase MDM2 as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP results in elevated mRNA and MDM2 protein levels. We further found that increased MDM2 levels lead to reduced P53 in NSCs, which alters NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for cancer, specifically inhibits MDM2 and P53 interaction, and rescues the neurogenic and cognitive deficits in FMRP-deficient mice. Our data unveil a regulatory role for FMRP and a potential new treatment for fragile X syndrome.

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…MDM2 overexpression has been observed in other diseases, including SLE and LN, pSS, FXS, RSH, atherosclerosis, MI, TAD, ARCI, and pterygium . Interestingly, MDM2 could be differentially expressed in different stages of the disease.…”

“…MDM2 has been demonstrated to be a potential target for the prevention and treatment of several noncancer diseases. MDM2 inhibitors, especially nutlin‐3a, have been evaluated in some specific diseases for protective and therapeutic effects . Nutlin‐3a is a first‐generation cis ‐imidazoline analog and an MDM2‐p53 binding inhibitor with high binding potency and selectivity that blocks the majority of the p53‐dependent functions of MDM2 .…”

“…Fragile X syndrome (FXS) is a genetic disorder that is caused by the loss of the fragile X mental retardation protein (FMRP) . Li et al have recently demonstrated that the loss of FMRP results in increased MDM2 expression, reduced p53 expression, and subsequent changes in the proliferation and differentiation of neural stem cells (Figure ). FMRP binds to MDM2 mRNA and decreases its stability in primary neural stem/progenitor cells (aNPCs).…”

“…Of interest, nutlin‐3a has been shown to rescue the proliferation and differentiation of Fmr1 KO aNPCs, without affecting wild‐type (WT) aNPCs. In vivo studies have shown that nutlin‐3a (10 mg/kg, intraperitoneal injection) rescues FMRP‐deficient mice to prevent neurodegenerative deficits …”

Sevoflurane Acts on Ubiquitination–Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice

“…We therefore did not perform the blood gas analysis of the mice in the current studies. In the intervention studies, the mice were treated with MG132 (0.5 mg/kg, dissolved in DMSO at the concentration of 0.3 ug/ul, Sigma-Aldrich, St. Louis, MO) 45,46 or Nutlin-3 (10 mg/kg, dissolved in DMSO at the concentration of 0.3 ug/ul, Sigma-Aldrich) 47 through intraperitoneal (IP) administration 30 minutes before each sevoflurane anesthesia on P6, P7 and P8. The mice in the control group received 0.1 ml DMSO solution (15 μl DMSO dissolved in 1 ml saline), which is the vehicle of MG132 and Nutlin-3.…”