Research interests

The neurotransmitter/neurohormone, dopamine, has roles in behavior, in learning and memory, and in response to stress. Research in my laboratory centers on the dopamine synthesis pathway and the pathway that synthesizes a regulatory cofactor, BH4, in Drosophila and three genes that are central to dopamine function, Punch, encoding GTP cyclohydrolase, pale, encoding tyrosine hydroxylase, and Catecholamines up, encoding a membrane protein that acts as a negative regulator of both pathways. Current projects are:

Dopaminergic neurons in the adult Drosophila brain

The regulation of response to environmental and oxidative stress. The BH4 and dopamine pathways are regulated in response to environmental and oxidative stress. Mutations in dopamine regulating genes that reduce dopamine pools cause increased susceptibility to stress, while those that increase dopamine levels confer protection against stress. We are interested in how response to stress is regulated and in studying the physiological basis for the effects of dopamine under stress conditions. We have also found that stress causes the loss of dopaminergic neurons, and we are examining the molecular events that result in dopamine neuron death. The effects of environmental conditions on these neurons suggests that this system may be a useful model for studying Parkinson's disease, which is associated with the selective loss of dopaminergic neurons.

Structure-function analysis of GTP cyclohydrolase. In humans, mutations in the GTP cyclohydrolase gene lead to two different diseases, hyperphenylalaninemia, which resembles phenylketonuria in its effects, and dopa-responsive dystonia, a neuromuscular disease. We are using the Drosophila model to study the molecular regulation of this enzyme by phosphorylation and by BH4 feedback inhibition.

Tracheal system of the Drosophila embryo

Protein interactions in dopamine regulation. Drosophila GTP cyclohydrolase, tyrosine hydroxylase, and Catecholamines up can physically associate in protein complexes. We are interested in mapping the regions of interaction, studying the regulation of these interactions, and understanding the consequences of complex formation for dopamine regulation.

The role of zinc. The membrane protein, Catecholamines up, has several structural features suggesting that it binds and transports zinc. While zinc is found in synaptic vesicles in mammalian neurons and can affect several components of dopamine signaling pathways, its precise role is unknown. We have found that Catecholamines up mutants are hypersensitive to zinc and that the metal causes neurological syndromes. We are interested in understanding why a protein predicted to be a zinc transporter is a negative regulator of dopamine production.

The role of the dopamine pathway in the development of trachea. The tracheal system is an elaborately branched network of tubes that function to deliver oxygen to all tissues in insects. The patterning of these tubes is genetically controlled, and many of these genes have counterparts in the development of another tubular network, blood vessels in vertebrates. Mutations in each of the dopamine regulating genes cause defects in tracheal development during embryogenesis. We are studying the cellular/molecular processes that utilize dopamine in tracheal development.

Selected publications

Zhang, Y.Q., D. B. Friedman, Z. Wang, E. Woodruff, III., L. Pan, J. O'Donnell, and K. Broadie, 2005. Protein expression profiling of the Drosophila Fragile X mutant brain reveals up-regulation of monoamine synthesis. Mol. Cell. Proteomics. 4: 278-290.

O'Donnell, J. M., Z. Wang, and A. Chaudhuri, 2004. Effects of perturbation of catecholamine regulation on resistance of Drosophila melanogaster to environmental stress. In: Pterins, Folates, and Related Biogenic Amines (Eds. N. Blau and Beat Thony), SPS Publications, Heilbronn, Germany, pp. 94-100.

Hepburn, D.D. D., J. Xiao, S. Bindom, J. B. Vincent and J. O'Donnell, 2003. Nutritional supplement chromium picolinate causes sterility and lethal mutations in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 100: 3766-3771.

O'Donnell, J. M., D. G. Stathakis, D. Burton, and Z. Chen, 2002. Catecholamines-up, a negative regulator of tyrosine hydroxylase and GTP cyclohydrolase I in Drosophila melanogaster. In: Chemistry and Biology of Pteridines, Kluwer Press, pp. 211-217.

Neckameyer, W.S., J. O'Donnell, Z. Huang, and W. Stark, 2001. Dopamine and sensory tissue development in Drosophila melanogaster. J. Neurobiol. 47: 280-294.

Krishnakumar, S. D. Burton, J. Rasco, X. Chen, and J. O'Donnell, 2000. Functional interactions between GTP cyclohydrolase I and tyrosine hydroxylase in Drosophila. J. Neurogenet. 14: 1:23.

Stathakis, D. G., D. Y. Burton, W. E. McIvor, S. Krishnakumar, T. R. F. Wright, and J. M. O'Donnell, 1999. The Catecholamines up (Catsup) protein of Drosophila melanogaster functions as a negative regulator of tyrosine hydroxylase activity. Genetics 153: 361-382.