Professor of Molecular Medicine and Genetics
Gregory Kapatos, Ph.D.
Gregory Kapatos, Ph.D.
540 East Canfield, 3353 Scott Hall
Detroit, MI 4820
Office Phone(313) 577-5965
Office Fax(313) 577-6739
My laboratory is interested in the general area of stimulus transcription coupling within monoaminergic neurons and has focused on GTP cyclohydrolase I (GCH1) as a model gene for study. GCH1 is the first and rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the essential pteridine cofactor for tyrosine hydroxylase and the production of dopamine (DA) by nigrostriatal DA (NSDA) neurons. Our research is clinically important because heterozygous mutations in GCH1 cause DOPA-responsive dystonia (DRD), an autosomal dominant disease that presents in childhood as dystonia and in adulthood as Parkinson's disease (PD). DRD is characterized by severe deficits in DA within intact NSDA neurons. Unaffected first-degree relatives of DRD patients have a higher incidence of Parkinsonism than do normal controls, suggesting an association between GCH1 and PD. Despite this strategic importance little is known about how NSDA neurons regulate GCH1 gene expression.
We are currently testing the hypothesis that GCH1 transcription within NSDA neurons is coupled to membrane potential and cAMP production. Our analysis of the cis-acting elements in the GCH1 proximal promoter that confer basal and cAMP-dependent transcription is nearly complete. It is possible that mutations in these cis-elements are responsible for human GCH1 deficiencies not linked to the GCH1 open reading frame. We are also studying the trans-acting factors recruited by these cis-elements, such as C/EBPb, Sp3 and NF-Y, because these proteins mediate cell type-specific cAMP-dependent GCH1 transcription and are therefore pharmacological targets for selectively enhancing GCH1 transcription within NSDA neurons. With the hypothesis that background genetic variability in GCH1 may promote susceptibility to familial Parkinsonism and idiopathic PD, in collaboration with researchers at the Mayo Clinic we are sequencing and functionally characterizing mutations in GCH1 proximal promoter and coding regions in familial Parkinsonism. Because association mapping is potentially a more powerful strategy for identifying genetic variability additional studies, we are also assessing genetic variability within the GCH1 gene in PD cases versus controls.
1973 B.S. in Psychology from the State University of New York at Cortland
1976 M.S. in Biopsychology from the University of Pittsburgh
1978 Ph.D. in Biology from the University of Pittsburgh
197 1978 - 1980 National Institute of General Medical Sciences Pharmacology Research Associate Fellowship (PRAT Fellow), Laboratory of Neurochemistry, National Institutes of Health (Sponsor: Dr. S. Kaufman)
1980 - 1982 Staff Fellow, Laboratory of Neurochemistry
National Institute of Mental Health
1982 - 1984 Senior Staff Fellow, Laboratory of Neurophysiology
National Institute of Neurological Diseases and Stroke
1978-1980 National Institute of General Medical Sciences Pharmacology Research Associate Fellowship (PRAT Fellow)
Swick, L. and Kapatos, G. A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions. J. Neurochem. 97:1447-1455, 2006.
Kapatos, G., Vunnava, P. and Wu, Y. Protein kinase A-dependent recruitment of RNA polymerase II, C/EBP and NF-Y to the rat GTP cyclohydrolase I proximal promoter occurs without alterations in histone acetylation. J. Neurochem. 101:1119-1133, 2007.
Wider, C., Melquist, S., Hauf, M., Solida, A., Cobb, S.A., Kachergus, J.M., Gass, J., Coon, K.D., Baker M., Cannon, A., Stephan, D.A., Schorderet, D., Ghika, J., Burkhard, P.R., Kapatos, G., Hutton, M., Farrer, M.J., Wszolek, Z.K., and Vingerhoets, F.J.G. Study of a Swiss Dopa-responsive dystonia family with a large deletion in GCH1. Ann. Neurol. Neurol. 69: 1-7, 2007.
Chandran, N.S., Vunnava, P., Wu, Y., and Kapatos, G. Specificity proteins Sp1 and Sp3 interact with the rat GTP cyclohydrolase I proximal promoter to regulate transcription. J. Neurochem.104:1233-1248, 2007.
Chandran N., Vunnava P., Wu, Y., and Kapatos, G. Regulation of GTP Cyclohydrolase I Gene Transcription by Diverse Signaling Pathways. In: Chemistry and Biology of Pteridines and Folates, Proceedings of the 13th International Symposium on Pteridines and Folates. G. Jansen and G.J. Peters eds., FST GmbH, Bonnigheim (2007) 286-299.