University of Wisconsin–Madison
College of Agriculture and Life Sciences | School of Medicine and Public Health

David Wassarman

Professor

dawassarman@wisc.edu

608-262-6648

Medical Genetics
Mechanisms underlying neurodegeneration

Address
4262 Genetics and Biotechnology Center
Education
B.S., Bates College, Ph.D., Yale University, Postdoctoral Research, Univ. of California - Berkeley
Department
Medical Genetics
Research Interests
Mechanisms underlying neurodegeneration
Research Fields
Disease Biology, Cell Biology, Development, Neuro & Behavioral Genetics, Drosophila

Research Description:
We are using fruit flies (Drosophila melanogaster) to understand human neuronal disorders. Currently, we are focusing on Ataxia-telangiectasia (A-T) and traumatic brain injury (TBI), both of which are characterized by neuronal degeneration (neurodegeneration) in the central nervous system. We are using genetic and molecular biology approaches to determine the cellular and molecular mechanisms that underlie neurodegeneration. The long-term goal of this research is to identify gene targets for diagnostic and therapeutic intervention in A-T and TBI.

Neurodegeneration in A-T

A-T is a recessive genetic disorder associated with neurodegeneration that worsens with age. The mutant gene responsible for A-T, ATM (A-T mutated), encodes a protein kinase that plays a central role in the response to DNA damage. Despite advances in our understanding of ATM activities, it remains unclear why neurodegeneration occurs in A-T. We have found that, as in humans, loss of ATM in flies causes neurodegeneration. Our genetic screen suggested that neurons die in A-T because they re-enter the mitotic cell cycle (Rimkus et al., 2008), and our molecular screen suggested that neurons die in A-T because of excessive activation of the innate immune response in glial cells (Petersen et al., 2012, 2013). Current projects are focused on understanding the molecular events that trigger neuron cell cycle re-entry and excessive activation of the glial cell innate immune response and how these events are connected.

Neurodegeneration in TBI

In the U.S., 2.5-6.5 million people are living with the consequences of TBI, including debilitating physical, cognitive, behavioral, and emotional outcomes. In collaboration with Dr. Barry Ganetzky’s laboratory (Genetics), we have been pursuing the idea of using flies to study TBI. Going into this, our thinking was that if we could develop a simple and reproducible method of inflicting TBI in flies and if the pathophysiological consequences of TBI in flies reproduce those in humans then we could use genetic approaches in flies to gain a deeper understanding of the secondary injury mechanisms that are triggered by primary injuries to the brain in humans. As described in our publications (Katzenberger et al., 2013, 2015), we have developed a spring-loaded device, called a High-Impact Trauma (HIT) device, to inflict TBI in flies. Moreover, we have observed that injuries inflicted by the HIT device lead to consequences that parallel those of TBI in humans. Through studies of genetic variants, we have uncovered novel information about the genes and biological processes associated with intestinal dysfunction following TBI. Thus, it appears that the fly model has enormous potential to advance our understanding of TBI in humans. Current projects are focused on identifying genetic risk factors and biomarkers for TBI as well as understanding the mechanistic links between aging and TBI.


Representative Publications:
Katzenberger, R. J., Ganetzky, B., and Wassarman, D. A. (2016) Age and diet affect genetically separable injuries that cause acute mortality following traumatic brain injury in Drosophila. G3 6, 4151-4166.

Katzenberger, R. J., Chtarbanova, S., Rimkus, S. A., Fischer, J. A., Kaur, G., Seppala, J. M., Swanson, L. C., Zajac, J. E., Ganetzky, B., and Wassarman, D. A. (2015) Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction. eLife 2015, 10.7554/eLife.04790.

Katzenberger, R. J., Loewen, C. A., Wassarman, D. R., Petersen, A. J., Ganetzky, B., and Wassarman, D. A. (2013) A Drosophila model of closed head traumatic brain injury. Proc. Natl. Acad. Sci. 110, E4152-E4159.

Petersen, A. J., Katzenberger, R. J., and Wassarman, D. A. (2013) The innate immune transcription factor Relish is necessary for neurodegeneration in a Drosophila model of Ataxia-telangiectasia. Genetics 194, 133-142.

Petersen, A. J., Rimkus, S. A., and Wassarman, D. A. (2012) ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration. Proc. Natl. Acad. Sci. 109, E656-E664.

Rimkus, S. A., Katzenberger, R. J., Trinh, A. T., Dodson, G. E., Tibbetts, R. S., and Wassarman, D. A. (2008) Mutations in String/CDC25 inhibit cell cycle reentry and neurodegeneration in a Drosophila model of Ataxia-telangiectasia. Genes Dev. 22, 1205-1220.