With a $90,000 grant from FRAXA Research Foundation over 2 years, Dr. Michael Wilhelm and his team at the University of Wisconsin studied a protein known as JNK, which is observed to be abnormally regulated in Fragile X. Like FMRP, it is involved in regulating dendritic protein synthesis, and so it may be a target for drug therapy in Fragile X.
Travis Schmidt, PhD
Postdoctoral Fellow
A hallmark of FXS is dysregulation of activity-dependent protein translation within dendritic spines, particularly of FMRP targeted mRNAs. Improved understanding of the signaling pathways linking synaptic activity to dendritic protein translation will increase our understanding of the pathobiology of FXS and provide novel therapeutic targets.
Protein kinase (phosphorylation) events occur rapidly following exogenous stimuli including synaptic stimulation. Several kinase signaling cascades are potently activated in response to mGluR5 stimulation and have been implicated in mGluR-dependent protein translation. Our research focused on regulation of novel kinases involved in the rapid, local translation of FMRP targets and the turnover of these proteins upon mGluR stimulation.
One FMRP target elevated in FXS is amyloid precursor protein (APP) and its cleavage product, amyloid β (Aβ). Increased APP and Aβ had been implicated in the perturbation of synaptic plasticity that occurs in Alzheimer’s disease and Trisomy 21. This suggested that normalization of APP in FXS may be a reasonable therapeutic goal as well as an indicator of general improvement in mGluR-dependent protein translation.
We planned to determine how a novel kinase pathway involved in mGluR-dependent protein translation within dendritic spines affects known FMRP targets, specifically APP. We used the fmr-1 KO mouse model which included both in vitro and in vivo experiments to determine 1) the local effects of kinase inhbition on FMRP regulated protein translation and turnover, and 2) the effects of kinase inhibition on the pathophysiology of the disease by evaluating the effects on the behavioral deficits seen in these mice, respectively.
