11/2/2018: This is an update on this ongoing project, as funding is renewed for a second year.
This 2017-18 grant of $90,000 was funded FRAXA with special funding Fragile X Research Foundation of Canada ($16,875 from FXRFC). Dr. Ilse Gantois was previously funded by FRAXA as a postdoctoral fellow in the Belgium lab of Dr. Frank Kooy.
A previous FRAXA grant to the Sonenberg lab has led to great interest in the available drug, metformin, as a potential treatment for Fragile X syndrome. Clinical trials of metformin are now in progress.
Nahum Sonenberg, PhD
Ilse Gantois, PhD
2017-2018 FRAXA Research Grant
$90,000 over 2 Years
Year 1 Co-Funded with the Fragile X Research Foundation of Canada
by Ilse Gantois, PhD
Insulin Signaling in Fragile X
Insulin signaling is known to be dysregulated in diabetes and cancer, and it has recently been implicated in cognitive dysfunctions in neurodegenerative disorders such as Alzheimer’s disease. Dysregulation of insulin signaling is likely also associated with Fragile X syndrome (FXS) and autism in general. We have shown that insulin receptors are upregulated in the FXS mouse model, and excessive insulin signaling was recently reported in the Fragile X fly model. Binding of insulin to the insulin receptor activates at least two separate pathways involved in regulating protein translation in brain cells. These two pathways are implicated in FXS.
Metformin to Regulate Insulin
The role and mechanism of action of increased insulin signaling in FXS and autism are as yet unknown. We will determine the mechanisms of dysregulated insulin pathway signaling in the FXS mouse model that can contribute to the autism-like phenotype. We are using genetic and pharmacologic strategies to decrease the amount of insulin receptor and downstream signaling in the FXS mouse model.
We have preliminary data showing that we can correct some specific behaviors in these mice. We will also investigate whether insulin receptors and insulin signaling are impaired in post-mortem brains of FXS patients. This work might reveal new strategies and drug targets for the treatment of FXS and autism spectrum disorders. In fact, based on these and other studies, Fragile X clinical trials are beginning with the available drug metformin, which is known to decrease insulin signaling and which is widely used to treat diabetes.
Ilse Gantois, PhD