With a $120,000 grant from FRAXA Research Foundation, Drs. Henri Tiedge and Jun Zhong studied the mechanisms by which local protein translation is repressed. This is an important function in all cells, and one which is clearly defective in Fragile X. There are multiple parallel mechanisms for keeping protein synthesis in check; one of them involves FMRP, and a similar mechanism involves the non-coding RNA, BC1. Study of the intersection of these mechanisms were hoped to provide targets for possible drug treatment of most basic defect in Fragile X. Results published.
The goal of this project was to test whether one can compensate for FMRP function in a postnatal brain through overproduction of BC1 RNA. Our previous results have shown that BC1 RNA and FMRP perform similar functions as repressors of group I mGluR-mediated translation. Lacking either BC1 RNA or FMRP leads to increased neuronal excitability, which can be rescued by mGluR5 inhibitor MPEP and inhibitors of the MAP kinase-signaling pathway. More importantly, effects of missing BC1 RNA and FMRP are compounded in mutant animals lacking both repressors, suggesting they functionally converge on common or overlapping targets. Therefore, it may be possible to produce more of one repressor to compensate for lack of the other.
To over-express BC1 RNA in a postnatal brain, we tried to introduce an inducible gene-expressing cassette into the mouse genome. We have shown that this expressing cassette produces high levels of BC1 RNA in a test cell line. Once integrated into the mouse genome, this system will allow us to examine whether overproduction of BC1 RNA can attenuate the epileptic phenotype observed in mice that lack FMRP. We hoped that results from this study may one day lead to a small RNA-based therapy for Fragile X syndrome.
Dr. Tiedge and colleagues published results in November 2010.