|Mind your STEP levels: Validation of a new drug target in Fragile X
by Susan Goebel-Goody, PhD, 9/4/2012
Researchers at the Yale University School of Medicine have identified striatal-enriched protein tyrosine phosphatase (STEP) as a new therapeutic target in Fragile X using genetic strategies in mice. STEP has emerged as a critical modulator of synaptic plasticity, or the ability of nerve cells to change in response to incoming stimuli. By negatively regulating the activity of key signaling molecules important for synaptic plasticity, STEP promotes the weakening of synapses. STEP is dysregulated in several neuropsychiatric conditions and appears to contribute to behavioral symptoms present in these disorders (1)
STEP was recently identified as a target of FMRP, the protein functionally absent in Fragile X (2). FMRP normally functions to suppress or inhibit the expression of its targets, acting as a means of ‘checks and balances’ to prevent aberrantly high levels of certain proteins in the synapse, or the site of connection between two nerve cells.
In Fragile X, this suppression is lacking, leading to increased expression of these targets. Work led by Dr. Susan Goebel-Goody, Associate Research Scientist at Yale, under the mentorship of Dr. Paul Lombroso, Professor in the Child Study Center, Departments of Neurobiology and of Psychiatry and Director of the Laboratory of Molecular Neurobiology at Yale University School of Medicine, demonstrated that the levels of STEP are elevated at baseline in the mouse model of Fragile X (referred to as Fmr1 KO) (3). They hypothesized that the weakened synaptic strength and behavioral abnormalities reported in Fragile X may be linked to excess levels of STEP.
In this study, the researchers reduced STEP genetically in Fmr1 KO mice as a way to simulate decreasing STEP activity with a drug. They found that reducing STEP levels reversed a wide range of Fragile X symptoms found in Fmr1 KO mice, including audiogenic seizures, social anxiety and hyperarousal to social stimuli, and non-social anxiety abnormalities. Altogether, their findings demonstrate the disease modifying potential for genetically reducing STEP in a breadth of robust behavioral phenotypes associated with Fragile X.
The study received international recognition at the 2011 Society for Neuroscience Annual Meeting in Washington, D.C., where Dr. Goebel-Goody was selected as one of 50 out of 16,000 presenters to discuss her findings at a ‘Hot Topics’ in neuroscience press conference on neurodevelopmental disorders. As a result, their work has received attention in both the Fragile X and autism fields. This work was initiated and supported by grants from FRAXA and the National Institutes of Mental Health.
Future directions are to identify small molecule inhibitors of STEP and determine if they are also effective at ameliorating behavioral abnormalities in STEP. The work by Dr. Goebel-Goody and Dr. Lombroso was responsible, in part, for heightened interest of STEP in drug discovery programs at pharmaceutical companies, and there are now at least three major pharmaceutical companies which have identified STEP in their drug development pipeline.
1. Goebel-Goody, S.M., Baum, M., Paspalas, C.D., Fernandez, S.M., Carty, N.C., Kurup, P., and Lombroso, P.J. (2012) Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacol Rev 64:65-87.
2. Darnell, J.C., Van Driesche, S.J., Zhang, C., Hung, K.Y., Mele, A., Fraser, C.E., Stone, E.F., Chen, C., Fak, J.J., Chi, S.W., Licatalosi, D.D., Richter, J.D., and Darnell, R.B. (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247-261.
3. Goebel-Goody, S.M., Wilson-Wallis, E.D., Royston, S., Tagliatela, S.M., Naegele, J.R., and Lombroso, P.J. (2012) Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model. Genes Brain Behav [Epub ahead of print]