Research in the O’Donnell lab takes diverse approaches to understanding homeostatic mechanisms in dopamine synthesis, transport and signaling in the genetic model organism, Drosophila melanogaster. We study networks of genes functioning in dopaminergic neurons and other dopamine-expressing cells, and in cells responding to dopamine dysregulation, as models of human diseases and developmental disorders. Current research areas in the lab include the following projects:

Gene-environment interactions in a Parkinson’s disease model

Parkinson’s disease is a common neurodegenerative disease, characterized by oxidative stress in and subsequent loss of dopaminergic neurons. Both genetic and environmental factors play roles in susceptibility to and progress of this disease. We employ the herbicide paraquat and other environmental toxins to investigate mechanisms of response to agents that damage dopaminergic neurons. Using genetic tools, we study the consequences of genetic variation in the dopamine synthesis and transport pathways and associated signal transduction pathways to identify genetic variation that confers either enhanced sensitivity or resistance to environmental factors that induce oxidative stress in dopaminergic neurons. We also employ this system to identify agents that slow or prevent disease progression and to dissect the mechanisms by which such agents act.

Neuroinflammation in neurodegenerative conditions

A key component of neuron loss in neurodegenerative diseases and neuronal injury is an inflammatory response that functions in the normal nervous system to remove unhealthy or damaged cells. In degenerative states, this innate inflammatory response is hyper-stimulated, resulting in acceleration of the loss of neurons and, therefore, progression of the disease. A well-conserved innate immune response system exists in Drosophila, and we have detected an inflammatory response to paraquat in our Parkinson’s disease model that parallels mammalian neuroinflammation in numerous ways. We are employing this system to identify genetic networks that function in this response and to screen compounds to their ability to ameliorate the destructive over-stimulation of the response.

Molecular mechanisms in autism

In an on-going collaboration, we have found interactions between a gene associated with autism spectrum disorders (ASD) and the dopamine homeostatic network. Changes in gene dosage of DUbe3a, the Drosophila form of a gene encoding an ASD-associated E3 ubiquitin ligase or over-expression of the human form, result in changes in the expression of genes regulating dopamine synthesis, providing a direct link to neurochemical changes in autism. We are conducting behavioral and neurochemical analyses of the mutant and over-expressing forms of Dube3a to investigate the mechanisms by which Dube3a regulates dopamine homeostasis.

Protein interactions in dopamine regulation

In humans, mutations in the GCHI gene, encoding GTP cyclohydrolase, lead to two different diseases, hyperphenylalaninemia, which resembles phenylketonuria, and dopa-responsive dystonia, a neuromuscular disease. We are using the Drosophila model to study the molecular regulation of this enzyme by phosphorylation and feedback inhibition. Drosophila GTP cyclohydrolase also physically associates with tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis and Catecholamines up, a negative regulator of both enzymes. 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.

• Bowling, K.M., Z. Huang, D. Xu, C.D. Funderburk, N. Karnik, F. Ferdousy, W. Neckameyer and J. M. O’Donnell (2008) Direct binding of GTP cyclohydrolase and tyrosine hydroxylase: Regulatory interactions between key enzymes in dopamine biosynthesis. J. Biol. Chem. 283: 31449-31459.
• Hsouna, A, H., Lawal, I. Izevbaye, T. Hsu, J. O’Donnell (2007) Drosophila dopamine synthesis pathway genes regulate tracheal morphogenesis. Devel. Biol. 308: 30-43.
• Chaudhuri, A., K. Bowling, C. Funderburk, A. Inamdar, and J. O’Donnell (2007) Interaction of genetic and environmental factors in a Drosophila parkinsonism model. J. Neurosci. 27: 2457-2467.
• Funderburk, C. D., K. Bowling, D. Xu, Z. Huang, and J. M. O’Donnell (2006) Atypical N-terminal extensions confer novel regulatory properties on GTP cyclohydrolase isoforms in Drosophila melanogaster. J. Biol. Chem. 281: 33302-33312.
• Stallings, D. M., D.D. Hepburn, M. Hannah, J. B. Vincent, and J. O’Donnell (2006) Nutritional supplement chromium picolinate generates chromosomal aberrations and impedes progeny development in Drosophila melanogaster. Mutation Res. 610:101-113.
• 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.
• Ajjuri, RR, Hall M, Reiter LT, O’Donnell JM (2014) Drosophila as a model for human movement disorders. In: Animal Models of Movement Disorders, M. LeDoux, ed. In Press.
• Ajjuri R and O’Donnell JM. (2013) Novel whole-tissue quantitative assay of nitric oxide levels in Drosophila neuroinflammatory response. J. Vis. Exp. 2013 Dec 4;(82). doi: 10.3791/50892
• Caldwell, KA, Shu Y, Roberts N, Caldwell GA, O’Donnell JM (2013) Invertebrate models of dystonia. Curr. Neuropharm. 11: 16-29.
• Inamdar AA, Chaudhuri A, O’Donnell JM (2012) The protective effect of minocycline in a paraquat-Induced Parkinson’s Disease model in Drosophila is modified in altered genetic backgrounds. Parkinson’s Dis. 2012; 2012:938528. doi: 10.1155/2012/938528.
• Ferdousy F, Bodeen W, Summers K, Doherty O, Wright O, Elsisi N, Hilliard G, O’Donnell JM, Reiter LT (2011) Dube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism. Neurobiol. Dis. 41: 669-677.
• Wakabayashi-Ito N, Doherty OM, Moriyama H, Gusella J, O’Donnell JM, Ito N (2011) dtorsin, a Drosophila homolog of early-onset dystonia DYT1, plays a novel role in the dopamine metabolism. PLoS One 6(10): e26183.
• Wang Z, Ferdousy F, Lawal H, Huang Z, Daigle JG, Izevbaye I, Doherty OM, Thomas J, Stathakis DG, O’Donnell JM (2011) Catecholamines up integrates dopamine synthesis and synaptic trafficking. J. Neurochem. 119: 1294-1305.
• Rahman M, O’Donnell JM, Brazel CS (2011) Cytotoxicity of plasticizers and ionic liquids containing ammonium, imidazolium and phosphonium-based cations using Drosophila melanogaster S2 cell culture. Chem. Eng. Technol. 34(3) 429-438.