Genetic and molecular mechanisms of age-dependent neurodegeneration
Progressive age-dependent deterioration and death of neurons are the devastating consequences of many human neurodegenerative syndromes of increasing medical importance. Still, despite enormous recent progress, we lack a comprehensive and detailed understanding of the various proteins and cellular pathways whose normal function is necessary to ensure neuronal viability. What is the basis of age dependence? Why are neurons often preferentially affected? Why are different subsets of neurons preferentially targeted in different syndromes? Are there multiple independent pathways that cause neuronal loss or do these pathways converge on a common mechanism?
We use the fruit fly, Drosophila melanogaster, as an experimental model system to address these and related questions to discover new information about the biological mechanisms that underlie age-dependent neurodegeneration. Our approach is to isolate mutants exhibiting neurodegeneration in this organism, molecularly identify the affected genes and proteins, and use this information to dissect the causative mechanisms. This approach closely parallels studies in humans where identification of patients manifesting neurodegenerative conditions is the starting point for subsequent studies to unravel the mechanisms responsible for disease manifestation. We have now identified a number of mutations in Drosophila that result in age-dependent neurodegeneration that provide us with many starting points for further investigation of the mechanisms that normally act to ensure protection and survival of neurons as they age.
Two mutants we are currently focusing on are wstd (wasted away) and comt (comatose), both of which exhibit shortened lifespan and age-dependent, progressive neurodegeneration. Our immediate goals are to determine the in vivo roles of the affected proteins using genetic, molecular, biochemical, and histological techniques to analyze how defects in these proteins result in the observed phenotypes. wstd encodes the glycolytic enzyme, triose phosphate isomerase (Tpi) responsible for the interconversion of DHAP (dihydroxyacetone phosphate) and GAP (glyceraldehyde 3-phosphate), only the latter of which is able to continue through glycolysis. Mutations of Tpi in humans result in Triosephosphate isomerase deficiency, characterized by early death and neurodegeneration but the underlying mechanism has remained unclear. We hypothesize that the enzymatic block in Tpi-deficient flies and humans leads to excess accumulation of methylglyoxal (MG), which reacts with target proteins to generate advanced glycation end products (AGEs) causing loss of protein activity, cross-linking, aggregation, and ultimately neuronal death. comt, which encodes NSF-1 (N-ethyl-maleimide sensitive fusion protein), exhibits a deficit in lysosomes and accumulation of ubiquitinated protein complexes in parallel with neurodegeneration. We hypothesize that comt is deficient in autophagy. We are now testing these hypotheses and investigating additional mechanisms of neuroprotection by similar analyses of other neurodegeneration mutants in our collection.
Both wstd and comt have direct links with human neurodegenerative disorders and we expect the same will be true for many of the other mutants we are investigating. Consequently, we expect that our proposed analyses will have broad biological and medical significance by advancing our understanding of the underlying molecules and mechanisms that maintain neuronal viability and integrity in both flies and people.
Ganetzky, B., & Hawley, R. S. (2016). The centenary of genetics: Bridges to the future. Genetics, 202(1), 15-23.
View publication via DOI: DOI:10.1534/genetics.115.180182
Hawley, R. S., & Ganetzky, B. (2016). Alfred sturtevant and george beadle untangle inversions. Genetics, 203(3), 1001-1003.
View publication via DOI: DOI:10.1534/genetics.116.191825
Katzenberger, R. J., Ganetzky, B., & Wassarman, D. A. (2016). Age and diet affect genetically separable secondary injuries that cause acute mortality following traumatic brain injury in Drosophila. G3, 6(12), 4151-4166.
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Babcock, D. T, Shen, W., & Ganetzky, B. (2015). NSF1 is neuroprotective in Drosophila by sustaining autophagy and lysosomal trafficking. Genetics, 199(2), 511-522.
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Katzenberger, R. J., Loewen, C. A., Bockstruck, R. T., Woods, M. A., Ganetzky, B., & Wassarman D.A. (2015). A method to inflict closed head traumatic brain injury in Drosophila. Journal of Visualized Experiments, 100, e52905.
View publication via DOI: DOI:10.3791/52905
Babcock, D. T., & Ganetzky, B. (2015). Non-cell autonomous cell death caused by transmission of huntingtin aggregates in Drosophila. Fly, 9(3), 107-109.
View publication via DOI: DOI:10.1080/19336934.2015.1118591
Babcock, D. T., & Ganetzky, B. (2015). Transcellular spreading of huntingtin aggregates in the Drosophila brain. Proceedings of the National Academy of Sciences of the United States of America, 112(39), E5427-5433.
View publication via DOI: DOI:10.1073/pnas.1516217112
Katzenberger, R. J., Chtarbanova, S., Rimkus, S. A., Fischer, J. A., Kaur, G., Seppala, J. M., Swanson, L. C., Zajac, J. E., Ganetzky, B., & Wassarman, D. A. (2015). Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction. Elife, 4, e04790.
View publication via DOI: DOI:10.7554/eLife.04790
Katzenberger, R. J., Ganetzky, B., & Wassarman, D. A. (2015). The gut reaction to traumatic brain injury. Fly, 9(2), 68-74.
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Sudmeier, L. J., Howard, S. P., & Ganetzky, B. (2015). A Drosophila model to investigate the neurotoxic side effects of radiation exposure. Disease Models and Mechanisms, 8(7), 669-677.
View publication via DOI: DOI:10.1242/dmm.019786
Sudmeier, L. J., Samudrala, S. S., Howard, S. P., & Ganetzky, B. (2015). Persistent activation of the innate immune response in adult Drosophila following radiation exposure during larval development. G3, 5(11), 2299-2306.
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Babcock, D. T., & Ganetzky, B. (2014). An improved method for accurate and rapid measurement of flight performance in Drosophila. Journal of Visualized Experiments, (84), e51223.
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Cao, Y., Chtarbanova, S., Petersen, A. J., & Ganetzky, B. (2013). Dnr1 mutations cause neurodegeneration in drosophila by activating the innate immune response in the brain. Proceedings of the National Academy of Sciences, 110(19), E1752-E1760.
View publication via DOI: DOI:10.1073/pnas.1306220110
Katzenberger, R. J., Loewen, C. A., Wassarman, D. R., Petersen, A. J., Ganetzky, B., & Wassarman, D. A. (2013). A drosophila model of closed head traumatic brain injury. Proceedings of the National Academy of Sciences, 110(44), E4152-E4159.
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Miller, D., Hannon, C., & Ganetzky, B. (2012). A mutation in Drosophila Aldolase causes temperature-sensitive paralysis, shortened lifespan, and neurodegeneration. Journal of Neurogenetics, 23(3-4), 317-327.
View publication via DOI: DOI:10.3109/01677063.2012.706346
Miller, D. L., Ballard, S. L., & Ganetzky, B. (2012). Analysis of synaptic growth and function in drosophila with an extended larval stage. The Journal of Neuroscience, 32(40), 13776-13786.
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Fergestad, T., Sale, H., Bostwick, B., Schaffer, A., Ho, L., Robertson, G.A., & Ganetzky, B. (2010). A Drosophila behavioral mutant, down and out (dao), is defective in an essential regulator of Erg potassium channels. Proceedings of the National Academy of Sciences, 107(12), 5617-5621.
View publication via DOI: DOI:10.1073/pnas.1001494107
Shen, W., & Ganetzky, B. (2010). Nibbling away at synaptic development. Autophagy, 6(1), 168-16.
View publication via DOI: DOI:10.4161/auto.6.1.10625
Shen, W., & Ganetzky, B. (2009). Autophagy promotes synapse development in Drosophila. Journal of Cell Biology, 187(1), 71-79.
View publication via DOI: DOI:10.1083/jcb.200907109
Fergestad, T., Olson, L., Patel, K.P., Miller, R., Palladino, M.J., & Ganetzky, B. (2008). Neuropathology in Drosophila mutants with increased seizure susceptibility. Genetics, 178, 947-956.
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Muhammad, A., Flores, I., Zhang, H., Yu, R., Staniszewski, A., Planel, E., Herman, M., Ho, L., Kreber, R., Honig, L. S, Ganetzky, B., Duff, K., Arancio, O., & Small, S.A. (2008). Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and AlphaBeta accumulation. Proceedings of the National Academy of Sciences, 105, 7327-7332.
O'Connor-Giles, K.M., & Ganetzky, B. (2008). Satellite signaling at synapses. Fly, 2(5).
O'Connor-Giles, K.M., Ho, L.L., & Ganetzky, B. (2008). Nervous wreck interacts with thick veins and the endocytic machinery to attenuate retrograde BMP signaling during synaptic growth. Neuron, 58(4), 507-518.
Fergestad, T., Ganetzky, B. & Palladino, M.J. (2006). Neuropathology in Drosophila membrane excitability mutants. Genetics, 172, 1031-1042.
View publication via DOI: DOI:10.1534/genetics.105.050625
Gnerer, J. P. P., Kreber, R. A., & Ganetzky, B. (2006). Wasted away, a Drosophila mutation in triosephosphate isomerase causes paralysis, neurodegeneration, and early death. Proceedings of the National Academy of Sciences, 103, 14987-14993.
View publication via DOI: DOI:10.1073/pnas.0606887103
Koh, Y.-H., Rehfeld, K. & Ganetzky, B. (2004). A Drosophila model of early-onset torsion dystonia suggests impairment in TGF-beta signaling. Human Molecular Genetics, 13, 2019-2030.
View publication via DOI: DOI:10.1093/hmg/ddh208
Palladino, M.J., Bower, J.E. Kreber, R., & Ganetzky, B. (2003). Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants. Journal of Neuroscience, 23, 1276-1286.
Palladino, M.J., Hadley, T.J. & Ganetzky, B. (2002). Temperature-sensitive paralytic mutants in Drosophila are enriched for those causing neurodegeneration. Genetics, 161, 1197-1208.
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