MDM2 inhibition rescues neurogenic and 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.
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA. Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
Yue
Y
Li
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
Michael E
ME
Stockton
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
Ismat
I
Bhuiyan
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA. Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
Brian E
BE
Eisinger
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA. Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
Yu
Y
Gao
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
Jessica L
JL
Miller
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
Anita
A
Bhattacharyya
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA. Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA. xinyu.zhao@wisc.edu.
Xinyu
X
Zhao
D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D051860:Fragile X Messenger Ribonucleoprotein 1; D007093:Imidazoles; D010879:Piperazines; D051736:Proto-Oncogene Proteins c-mdm2; C497684:Fmr1 protein, mouse; C482205:nutlin 3