Medical Student Research Fellowship for Summer 2007

Mentor: Dr. Paula G. Ulery
Department: Neurology and Psychiatry
Room number: ND4.136A (Lab) ND12.120A (office)
Mail Code: 8813
Phone number: 5-6020
E-mail: paula.ulery@utsouthwestern.edu
Project title: Role of Syntaxin-1 Phosphorylation on Neurotransmitter Release: implications for Schizophrenia

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): APN 1133 06 01 1

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects). The project is both patient-based (post mortem tissue analysis) and animal-based.

Brief Description of Project:

Schizophrenia is one of the most devastating human diseases. In fact, Schizophrenia ranks among the top 10 causes of disability in developed countries worldwide. While some aspects of the disease (mainly the psychosis) are amenable to treatment, its most chronic and disabling aspects (i.e., negative and cognitive symptoms) are not. Recent advances in our understanding of the brain areas and genes involved in schizophrenia have provided exciting leads for new research (Harrison and Weinberger 2005). It is now more possible than ever before to dissect the molecular mechanisms underlying this complex and puzzling disease. Among the various aspects of brain function that are probably aberrant in schizophrenia, neurotransmitter release, an obligatory event in synaptic activity, is a promising target of research. In fact, several of the molecules involved in this process have been associated with schizophrenia (Eastwood 2004; Owen, O'Donovan et al. 2005). Although researchers have unveiled many of the important components of the pre- and post-synaptic machineries, the regulation of their activities, particularly for the pre-synaptic proteins, remains unclear. That is the case of the pre-synaptic protein, syntaxin-1 (Stx-1); a key player in neurotransmitter release (Wu, Fergestad et al. 1999). Postmortem studies have detected increased syntaxin immunoreactivity in the cingulate cortex of schizophrenic brains (Gabriel, Haroutunian et al. 1997; Honer, Falkai et al. 1997), higher syntaxin mRNA levels in the temporal cortex of young schizophrenia patients (Sokolov, Tcherepanov et al. 2000), and a recent study has shown a genetic association between the syntaxin-1A gene and schizophrenia (Wong, Trakalo et al. 2004). While little is known about how Stx-1 function is regulated, it has been shown that Stx-1 is phosphorylated in vivo on Ser14 (Foletti, Lin et al. 2000), and that most likely the kinase involved is casein kinase 2 (CK2) (Dubois, Kerai et al. 2002).
Our working hypothesis is, on the one hand, that synaptic transmission is abnormal in the schizophrenic brain, and that this is due (at least in part) to aberrant neurotransmitter release. On the other hand, we hypothesize that Stx-1 may be one of the malfunctioning synaptic components. Since previous research has shown that Stx-1 is phosphorylated in vivo, and phosphorylation is such a universal means of regulating a protein's function, we propose that Stx-1 phosphorylation is altered in schizophrenia and that this contributes to the aberrant brain function characteristic of the disease. To this end we have developed a phospho-specific antibody against phospho-Ser14-Stx-1 and are using it to asses Stx-1 phosphorylation in post-mortem brain tissue from schizophrenics and matched controls. Unveiling how phosphorylation may regulate Stx-1 would lead not only to a greater understanding of normal brain function but, as it has been the case for HIV/AIDS and various cancers, it could lead to successful kinase and/or phosphatase-based therapies.

References

DeGiorgis, J. A., H. Jaffe, et al. (2005). "Phosphoproteomic analysis of synaptosomes from human cerebral cortex." J Proteome Res 4(2): 306-15.
Dubois, T., P. Kerai, et al. (2002). "Identification of syntaxin-1A sites of phosphorylation by casein kinase I and casein kinase II." Eur J Biochem 269(3): 909-14.
Eastwood, S. L. (2004). "The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame?" Int Rev Neurobiol 59: 47-72.
Foletti, D. L., R. Lin, et al. (2000). "Phosphorylated syntaxin 1 is localized to discrete domains along a subset of axons." J Neurosci 20(12): 4535-44.
Gabriel, S. M., V. Haroutunian, et al. (1997). "Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia." Arch Gen Psychiatry 54(6): 559-66.
Harrison, P. J. and D. R. Weinberger (2005). "Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence." Mol Psychiatry 10(1): 40-68; image 5.
Honer, W. G., P. Falkai, et al. (1997). "Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia." Neuroscience 78(1): 99-110.
Owen, M. J., M. C. O'Donovan, et al. (2005). "Schizophrenia: a genetic disorder of the synapse?" Bmj 330(7484): 158-9.
Sokolov, B. P., A. A. Tcherepanov, et al. (2000). "Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients." Biol Psychiatry 48(3): 184-96.
Wong, A. H., J. Trakalo, et al. (2004). "Association between schizophrenia and the syntaxin 1A gene." Biol Psychiatry 56(1): 24-9.
Wu, M. N., T. Fergestad, et al. (1999). "Syntaxin 1A interacts with multiple exocytic proteins to regulate neurotransmitter release in vivo." Neuron 23(3): 593-605.

Previous Research Activities or Publications with Medical Students:

None (new faculty)

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