Adolescent Psychiatry; Alzheimer Disease; Child Psychiatry; Fragile X Syndrome; Neuropharmacology; Neurosciences; Parkinson Disease; Psychiatry; Schizophrenia; Protein Tyrosine Phosphatases, Non-Receptor
Child Study Center: Family, Genetic and Molecular Research | Lombroso Lab | NIMH Research Training Program in Childhood-onset Neuropsychiatric Disorders | Tourette’s Syndrome & Obsessive-Compulsive Disorders
The laboratory focuses on mammalian learning and how these processes are disrupted in various neuropsychiatric disorders. We are interested in several disorders including fragile X syndrome, schizophrenia, Parkinson's disease, and Alzheimer's disease. Central to this investigation is a brain-specific protein tyrosine phosphatase called STEP and its role in regulating intracellular signaling.
Our earlier work showed that STEP regulates ERK1/2 and Fyn by dephosphorylating and inactivating them. STEP also regulates the cell surface expression of AMPA and NMDA glutamate receptors and leads to their internalization. Signals that lead to STEP inactivation potentiate learning, whereas signals that lead to the STEP activation oppose the development of synaptic plasticity. We use biochemical, molecular, immunocytochemical, and behavioral techniques in animal models to address the role that STEP plays in regulating aspects of learning.
On-going projects include the involvement of STEP in several neurospychiatric and neurodegenerative disorders including: Fragile X syndrome, Alzheimer's disease, Parkinson's disease, and schizophrenia. We are characterizing novel STEP inhibitors in animal models of these disorders and determining their ability to reverse cognitive and behavioral deficits; STEP's regulation of glutamate receptor trafficking; the regulation of STEP by ubiquitination and phosphorylation.
Specialized Terms: Translational Neuroscience; Identification of small molecule inhibitors of STEP; Child and adolescent psychiatry; Neuropharmacology
Extensive Research Description
The Lombroso Lab studies how we normally learn and how these processes are disrupted in various neuropsychiatric disorders. We are interested in a number of disorders including Tourette’s syndrome, obsessive-compulsive disorder, autism, as well as drug addiction and Alzheimer’s disease. Our work focuses on a brain-specific protein tyrosine phosphatase called STEP and its role in regulating intracellular signaling.
Studies have shown that STEP expression is disrupted in over 10 different disorders. Some have have elevated levels of STEP while others have lower expression. Thus the current model is that optimal levels of STEP are required for proper synaptic function. Substrates of STEP include the kinases ERK1/2, Pyk2 and Fyn and dephosphorylation inactivates these enzymesem. STEP also regulates the cell surface expression of AMPA and NMDA glutamate receptors, and leads to their endocytosis. Signals that lead to the inactivation of STEP potentiate learning, while signals that lead to the activation of STEP oppose the development of synaptic plasticity. We use biochemical, molecular, immunocytochemical, and behavioral techniques to address the role that STEP plays in regulating aspects of learning.
- Identification and characterization of STEP inhibitors.
- Characterization of the STEP knock-out mouse.
- Regulation of glutamate receptor trafficking by STEP.
- Role of STEP in different disorders
- Phosphorylation of STEP and function of phosphorylation at specific sites.
- Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, Kanyo J, Zhang Y, Seyb K, Onomenyi C, Foscue E, Anderson GM, Gressack J, Cuny GD, Glicksman MA, Greengard P, Lam T, Nairn AC, Tautz L, Ellman JA, Lombroso PJ (2014) Inhibitors of the tyrosine phosphatase STEP reverse cognitive deficits in a mouse model of Alzheimer’s disease. PLoS Biology 12(8):e1001923. doi: 10.1371/journal.pbio.1001923. PMCID4122355
- Chiodi V, Mallozzi C, Fan Chen J, Ferrante A, Lombroso PJ, Di Stasi AM, Domenici MR, Popoli P (2014) Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP. Neuropsychopharmacology. 39:569-578 PMCID3895235
- Baguley TD, Xu HC, Chatterjee M, Lombroso PJ, Ellman J (2013) Substrate-based fragment identification for the development of selective, nonpeptidic inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase. J Med Chem 56:7636-7650. PMCID in progress.
- Deb I, Manhas N, Poddar R, Allan AM, Rajagopal S, Lombroso PJ, Rosenberg GA, Jalil EC, Paul S (2013) Neuroprotective role of STEP, a brain-enriched tyrosine phosphatase, in focal cerebral ischemia. J Neuroscience 33:17814-17826. PMCID3818554.
- Goebel-Goody SM, Baum M, Paspalas C, Carty NC, Fernandez S, Kurup P, Lombroso PJ (2012) Therapeutic implications for STriatal-Enriched protein tyrosine Phosphatase (STEP) in neuropsychiatric disorders. Pharmacological Reviews 64:65-87. PMCID3250079.
- Carty NC, Xu J, Kurup P, Goebel-Goody SM, Brouillette J, Austin DR, Yuan P, Chen P, Chen G, Correa PR, Pittenger C, Lombroso PJ (2012) The tyrosine phosphatase STEP: Implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Translational Psychiatry 2:e137 doi:10.1038/tp.2012. 63. PMCID3410627.
- Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA (2012) Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington’s disease mouse model. Human Molecular Genetics 21:3739-52 PMCID3412376
- Venkitaramani DV, Moura PJ, Picciotto MR, Lombroso PJ (2011) Striatal-Enriched protein tyrosine Phosphatase (STEP) knockout mice have enhanced hippocampal memory. Eur J Neurosci. 33:2288-2298. PMCID3118976.
- Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas J, Lombroso PJ, Alberch J, Pérez-Navarro E (2011) STEP expression and activity in Huntington’s disease-a STEP in the resistance to excitotoxicity. J Neuroscience 31:8150-8162. PMCID3472648.
- Zhang YF, Kurup P, Xu J, Carty N, Fernandez S, Nygaard HB, Pittenger C, Greengard P, Strittmatter S, Nairn AC and Lombroso PJ (2010) Genetic reduction of STEP reverses cognitive and cellular deficits in a mouse model of Alzheimer’s disease. PNAS.
- Kurup P, Zhang YF, Xu J, Venkitaramani DV, Haroutunian V, Nairn A, Lombroso PJ (2010) Abeta-mediated NMDA receptor endocytosis in Alzheimer’s disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neuroscience 30:5948-5957.
- Xu J, Kurup P, Zhang YF, Goebel-Goody S, Wu P, Hawasli AH, Baum M, Bibb J, Lombroso PJ (2009) Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neuroscience 29:9330-9343.
- Zhang Y, Vankitaramani DV, Gladding CM, Zhang YF, Kurup P, Molnar E, Collingridge GL, Lombroso PJ (2008) The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation. J Neuroscience 28:10561-10566.
- Choi YS, Lin SL, Lee B, Kurup P, Cho HY, Naegele JR, Lombroso PJ, Obrietan K. (2007) Status epilepticus-induced somatostatinergic hilar interneuron degeneration is regulated by striatal enriched protein tyrosine phosphatase. J Neurosci 27:2999-3009.
- Braithwaite, S., Paul, S., Nairn, A., and Lombroso, P.J. (2006). Learning and memory: One STEP at time. Trends Neurosci. 29:452-458.
- Paul S, Olausson P, Venkitaramani D, Ruchkina I, Moran TD, Mills E, Tronson N, Hakim S, Salter MW, Taylor J and Lombroso PJ (2007) The protein tyrosine phosphatase STEP gates long-term potentiation and fear memory in the lateral amygdala. Biological Psychiatry 61:1049-1061.[PDF]
- Snyder, E.M., et al. (2005). Regulation of NMDA receptor trafficking by beta-amyloid. Nature Neurosci. 8:1051-1058.