With a $90,000 grant from FRAXA Research Foundation, Dr. Peng Jin’s team from Emory University School of Medicine found that fragile X causes an increase production of new cells, so they tested large numbers of drugs to find those that can correct this. This high throughput drug screen uses neural stem cells from fragile X knockout mice to identify small molecules which may be therapeutic in fragile X.
Neurogenesis, or the generation of new neurons, persists at a low level throughout life in two germinal zones of the brain, the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles Although the specific purpose of adult neurogenesis was not fully clear, mounting evidence pointed to its potentially important roles in adult neuroplasticity. The cellular basis of adult neurogenesis is neural stem/progenitor cells (NSPCs) residing in the two germinal zones. Our previous studies have shown that the loss of Fmrp led to increased proliferation and altered fate specification of aNSPCs both in vitro and in vivo. Fmrp-deficient aNSPCs displayed increased proliferation and decreased neuronal differentiation, but increased glial differentiation. These data unveil a novel regulatory role of Fmrp in adult neurogenesis and suggested that the altered adult neurogenesis in the absence of Fmrp could contribute to the pathogenesis of fragile X syndrome.
We established high throughput screening system using lentivirus expressing NeuroD1 promoter-luciferase reporter in cultured primary NSPCs. Through screening ~2,400 small molecules, we identified several small molecules that could rescue the phenotype of Fmr1 KO aNSPCs. We are in the process of validating these small molecules in different systems, and continuing to screen additional small molecule libraries. The identification of these small molecules should provide additional therapeutic approaches for the treatment of fragile X syndrome.