Paul Lombroso, PhD—Yale Child Study Center
STEP: A novel therapeutic drug target in Fragile X Syndrome

Paul Lombroso, PhD, Principal Investigator
Deepa Venkitaramani, PhD, FRAXA Postdoctoral Fellow (2008)
Susan Goebel Goody, PhD, FRAXA Postdoctoral Fellow (2009-2012)

FRAXA Awards:

$85,000 in 2010
$85,000 in 2009
$84,000 in 2008


Dr. Lombroso is a Child Psychiatrist and Molecular Biologist at Yale University. He was trained at Harvard, Albert Einstein and Rockefeller University. His interests are in how we normally learn, and how these processes may be disrupted in childhood developmental disorders.

Dr. Susan Goebel-Goody completed her postdoctoral studies in Dr. Lombroso's lab in 2012. She won international recognition for this work (see below) and currently works for Pfizer in drug development.
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.

 

References

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]
STEP: A novel therapeutic drug target in Fragile X Syndrome

by Susan Goebel-Goody, 4/1/2010

Despite significant advancements in understanding the cause of Fragile X Syndrome (FXS), effective treatment strategies for patients are lacking. 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 behavioral 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 now 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. This work has tremendous therapeutic potential for patients with FXS since pharmaceuticals targeting STEP could be developed. Moreover, given that FXS remains the most inherited form of autism, results from this study could have broader implications in the treatment of autism and other related disorders.

by Paul Lombroso, 5/1/2008

STriatal Enriched protein tyrosine Phosphatases (STEP) is a brain-specific phosphatase that regulates key signaling proteins involved in the development of synaptic plasticity. Of particular relevance to this proposal is the finding that STEP regulates the trafficking of glutamate receptor to and from the surfaces of neurons. The presence of glutamate receptors at active synapses on neuronal surfaces is required if we are to turn short-term memories into long-term memories. The absence of these receptors on neuronal membranes is proposed to be an underlying cause for the cognitive and behavioral symptoms that appear in affected individuals with fragile X syndrome. The reason that we propose that STEP might be involved in this disorder is the recent finding that STEP is rapidly translated in response to activation of a group of receptors called mGluRs. Specifically, stimulation of these receptors results in an increase in STEP protein. Our model is that FMRP (the protein mutated in fragile X syndrome) normally binds to STEP message and inhibits its translation. In the absence of FMRP, STEP translation is inappropriately increased. The over-expression of STEP protein in turn promotes the loss of glutamate receptors from neuronal surfaces. The implication of this model is that lowering STEP levels may protect against some of the biochemical and behavioral effects seen in Fmr1 mutant mice. The present proposal will test this hypothesis by reducing STEP levels through genetic means in an animal model. We have developed a mouse that does not express STEP protein (a STEP knockout). If we now mate these mice to the fragile x syndrome mouse model (the Fmr1 mouse), we will generate mice that have both a mutation in the Fmr1 gene and no expression of STEP protein. Our prediction is that STEP will no longer be present and will not remove glutamate receptors from neuronal surfaces. We will test whether we have reversed some of the behavioral and cognitive deficits found in the parental Fmr1 mice. This is a novel hypothesis on the pathophysiology of fragile X syndrome. If STEP mediates the loss of glutamate receptors from neuronal surfaces, then it implies that lowering STEP function may have therapeutic value. The Lombroso laboratory currently has a separate line of investigation looking for small molecule inhibitors of STEP, and these will be available for testing in the near future.