Targeting AMP-Activated Protein Kinase Pathway in Fragile X Syndrome

With a $100,000 grant from the FRAXA Research Foundation in 2015, Dr. Peter Vanderklish at Scripps explored a novel strategy to treat fragile X syndrome: AMPK activators. The good news is that there are FDA approved (for example, metformin) and naturally occurring AMPK activators (such as resveratrol, found in red wine).

Peter Vanderklish, PhD lab
$100,000 Grant
Peter Vanderklish, PhD
Principal Investigator
See-Wing Chan
Research Technician
Julie Pilotte, PhD
FRAXA Fellow
Scripps Research Institute
2015 FRAXA Research Grant
$100,000

We have found that a key negative regulator of several signaling pathways, the AMP-activated protein kinase (AMPK), is underactive in the brains of Fragile X mice. We have also found that AMPK is stimulated by receptors implicated in Fragile X. Intriguingly, activation of AMPK induces potentially beneficial changes in several therapeutically relevant FMRP targets, notably PDE4, GSK3 which are being studied by other FRAXA teams.

So, we propose that AMPK activators can be used as a multi-potent pharmacological strategy to normalize signaling activity, rescue exaggerated translation, and correct the expression of critical FMRP targets. This approach has the added advantage that it can normalize translation coupled to multiple receptors without affecting their other functions (unlike mGluR antagonists, for example).

Our project is designed to define the extent and basis of deficient AMPK activity in the Fragile X mouse brain, its impact on abnormalities in translation rate and signaling, and the ability of several types of AMPK-activating drugs to rescue core translational, synaptic and behavioral phenotypes. We employ biochemical, molecular, histological, pharmacological and behavioral approaches in these studies, making use of antibodies that report the activation state of AMPK and the mTOR and ERK1/2 pathways, and a diverse set of AMPK activators.

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FRAXA-funded researchers around the world are leading the way towards effective treatments and ultimately a cure.