Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome
Paul Lombroso, PhD
Principal Investigator
Manavi Chatterjee, PhD
FRAXA Postdoctoral Fellow 2014-15
Susan Goebel Goody, PhD
FRAXA Postdoctoral Fellow 2009-12
Deepa Venkitaramani, PhD
FRAXA Postdoctoral Fellow 2008
Yale University
New Haven, CT
2014-2015 Grant Funding: $90,000
2008-2011 Grant Funding: $259,000
Summary
Dr. Paul Lombroso and his team at Yale University investigated whether inhibiting STEP (STriatal-Enriched protein tyrosine Phosphatase) could reduce behavioral abnormalities in Fragile X syndrome. Results published.
Several major pharmaceutical companies are developing STEP inhibitors, so these may be potential treatment options.
The Results
Results were published in Neuropharmacology in 2018: STEP inhibition reverses behavioral, electrophysiologic, and synaptic abnormalities in Fmr1 KO mice
The Science
by Paul Lombroso, 2014
We are using a pharmacological inhibitor of STEP to reduce behavioral abnormalities in Fragile X mice. We identified TC-2153 as a novel STEP inhibitor which can cross the blood brain barrier and inhibits STEP in normal (wildtype) mice. We will administer TC-2153 to adult Fragile X mice to determine whether pharmacologic inhibition of STEP reduces FXS-related deficits. This work will assess the disease modifying potential for STEP inhibitors in FXS and validate STEP as a target of drug discovery.
by Susan Goebel-Goody, 2012
A priority of FXS research is to discover mRNAs that are regulated by FMRP, the protein that is functionally absent in FXS, since these are potential therapeutic targets.
Our team is testing the hypothesis that reducing and/or inhibiting STriatal-Enriched tyrosine Phosphatase (STEP) rescues some of the deficits present in the mouse model for FXS. STEP is located in neurons at the synapse, the structure permitting communication between neurons. The synapse is highly plastic and strengthens or weakens in response to stimuli from other neurons. STEP opposes synaptic strengthening and promotes synaptic depression by facilitating internalization of the AMPA receptor subtype of glutamate receptors.
Normally, FMRP binds to STEP mRNA and suppresses its translation into protein. As a result, STEP protein is elevated in FXS in absence of functional FMRP. Increased levels of STEP protein may therefore contribute to the weakening of synaptic connections in FXS.
Using a genetic approach to eliminate STEP levels in FXS mice, we have exciting data which demonstrates that loss of STEP renders FXS mice less susceptible to audiogenic seizures. This data validated STEP as a target for drug discovery, and we have obtained a STEP compound inhibitor from an initial screen of 150,000 compounds. Our proposal will examine whether genetically reducing STEP protein levels and/or pharmacologically inhibiting STEP activity reverses the anxiety, cognitive, and socialization deficits present in FXS mice. We will also determine if reducing STEP levels and/or activity reverses the exaggerated metabotropic glutamate receptor-dependent long term depression found in FXS mice.
Investigating the role of STEP in FXS addresses a key unanswered question in FXS research with clear therapeutic implications. Namely, it links over-expression of STEP with the enhanced AMPA receptor internalization and exaggerated long term depression present in FXS mice.
