A Neuron to Remember: Correcting Imbalances in Fragile X Syndrome

fragile X neurons - Emily Osterweil, PhD.

University of Edinburgh researcher Emily Osterweil, PhD, probes the brain’s biochemistry to correct imbalances

We know the “X” in fragile X refers to the X chromosome, but it could just as easily refer to the unknown.Such as why do people with fragile X have an excessive production of new proteins in their brains that lead to imbalances?

That question is being dissected in the lab of Emily Osterweil, PhD, chancellor’s fellow, Centre for Integrative Physiology, University of Edinburgh, UK.

Dr. Osterweil is using insights from previous experiments to identify new treatment strategies for fragile X. Her goal is to understand the biochemistry of the brain better. She aims to correct those imbalances by making new proteins from existing messenger RNA, to snap neurons into “remembering” what happened to them before.

FRAXA Fellowship Awarded May 2016, Renewed May 2017

Enhancement of NMDA receptor signaling for the treatment of fragile X syndrome

Principal Investigator
Emily Osterweil, PhD

Postdoctoral Fellow
Stephanie Barnes, PhD

University of Edinburgh
$90,000 over 2 years

research fragile X neurons osterweil lab

Normalizing Fragile X Neurons

Dr. Osterweil’s goals are to figure out how to return neurons back to normal, so they’re producing the right amounts of protein, and to develop new treatment strategies, including drugs that might be re-purposed for the treatment of fragile X.

“We’ve shown targeting the ERK pathway can correct protein synthesis and seizure phenotypes in the mouse model,” said Dr. Osterweil, who earned a BA in Biology, Oberlin College, and was a Postdoctoral Associate, Picower Institute for Learning and Memory, MIT. “We used this to identify new clinically viable solutions for reducing ERK in fragile X. This led us to test the statin drug Lovastatin, a well-tolerated cholesterol-lowering drug that also inhibits the ERK pathway. In subsequent work, we showed Lovastatin helps address multiple pathologies in the fragile X mouse model.

Thanks to this work, FRAXA has initiated clinical trials of Lovastatin in fragile X syndrome.

“Neurons are hypersensitive to stimulation of metabotropic glutamate receptors (mGluRs) and the ERK signalling pathway. Normalizing protein synthesis using inhibitors to the mGluR or the ERK signalling pathway can correct many pathologies in the fragile X mouse model. We are testing other biochemical strategies to re-balance protein synthesis and new strategies for normalizing protein synthesis in the fragile X brain, including the role of NMDA type glutamate receptor.”

Research is the Key to Solving Fragile X

Research is the key to solving fragile X, according to Dr. Osterweil.

“Good research comes at a cost and it is an ever-present struggle to obtain enough financial support to keep the laboratory running,” she said. “Thankfully, there are foundations like FRAXA that provide much-needed support for the experiments that are crucial to understanding how to treat fragile X and other neurodevelopmental disorders. FRAXA has been a constant supporter of my research, has helped support some fantastic postdoctoral researchers, and has helped us develop new lab techniques to really understand what’s happening in individual fragile X neurons.”

Dr. Osterweil became interested in cell biology of neurons during her doctoral work in Neuroscience at Yale University, in particular that new protein synthesis could be used by neurons to form memories.

“I wanted to better understand how signalling between neurons is enhanced or disrupted by changes in protein synthesis,” she said. “In my postdoctoral work, I sought to test the idea that dysfunctional protein synthesis was a core contributor to the symptoms of fragile X.”

Dr. Osterweil said she is optimistic there will be advanced treatments for fragile X in the near future.

“The scientific community studying fragile X is uniquely close-knit,” she said. “We are united in the goal of treating this disorder, and that adds an extra level of motivation that enhances everyone’s research. As an early career researcher, it has been very beneficial to be a part of the fragile X research community.”

Emily Osterweil’s page at University of Edinburgh

Explore Current Fragile X Research

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