transgenic models for human neurodegenerative disease
The laboratory focuses on using Drosophila melanogaster to a tool to define genes important for human brain disease. A class of human neurodegenerative diseases involves expansion of a polyglutamine repeat within the various disease proteins. This polyglutamine expansion results in a dominant, toxic property of the disease protein, leading to neural degeneration. Huntington's disease is of this class. We have recreated this class of human neurodegenerative disease in Drosophila by expressing in flies one of these human disease proteins with an expanded polyglutamine run. Whereas expression of the protein with a normal polyglutamine repeat has no effect, expression of the protein with an expanded polyglutamine repeat results in late onset, progressive degeneration in the nervous system. This indicates that the molecular mechanisms of human polyglutamine disease are conserved in Drosophila. Hence, we are now using Drosophila in order to define genes involved in the mechanisms and progression of polyglutamine disease, identify suppressor mutations that can prevent or delay brain degeneration, and extending these studies to additional diseases like Parkinson’s disease and motor neuron diseases. We are also expanding into neural injury and aging models in Drosophila by analyzing the nervous system with age. We hope that these studies will lead insight into neural decline with aging, providing an approach for new treatments.
Lessing, D. and Bonini, N.M. (2009) Maintaining the brain: Insight into human neurodegeneration from Drosophila mutants. Nature Rev Genet 10: 359-370.
Li LB, Yu Z, Teng X and Bonini NM (2008) RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature, 453:1107-11. Epub 2008 Apr 30
Jung J and Bonini NM (2007) CREB-binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease. Science 315: 1857-1859..
Bilen J, Liu N, Burnett BG, Pittman RN, and Bonini NM(2006) MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Molecular Cell 24: 157-63.
Meulener M, Xu K, Thomson L, Ischiropoulos H and Bonini NM (2006) Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc. Natl. Acad. Sci USA 103: 12517-22.
Warrick JM, Gordesky-Gold B, Morabito L, Faust L, Paulson HL, and Bonini NM. (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Molecular Cell 18: 37-48.
Auluck P.K., and Bonini N.M. 2002. Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8:1185-6.
Auluck P.K., Chan H.Y., Trojanowski J.Q., Lee V.M., andBonini N.M. 2002. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295:865-8.
Bonini N.M. 2002. Chaperoning brain degeneration. Proc Natl Acad Sci U S A 99 Suppl 4:16407-11.
Chan H.Y., Warrick J.M., Andriola I., Merry D., and Bonini N.M. 2002. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 11:2895-904.
Chan H.Y., Warrick J.M., Gray-Board G.L., Paulson H.L., andBonini N.M. 2000. Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9: 2811-20.
Fortini M.E. and and N.M. Bonini 1999. Modeling human neurodegenerative diseases in Drosophila: on a wing and a prayer. Trends in Genetics 16:161-167.
Warrick J., Chan H.Y.E., Chai Y., Paulson H. and N.M. Bonini1999. Suppression of polyglutamine disease in Drosophila by the molecular chaperone hsp70. Nature Genetics 23:425-428.
Warrick J.M., Paulson H., Gray-Board G.L., Bui Q.T., Fischbeck K., Pittman R.N., and N.M. Bonini 1998. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93:939-949.
Warrick J.M., Paulson H., Gray-Board G.L., Bui Q.T., Fischbeck K., Pittman R.N., and N.M. Bonini 1998. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93: 939-949.
BIOL 221: Molecular Biology and Genetics
- Ellison Medical Foundation Senior Scholar Award in Aging Research
- NIH EUREKA
- David and Lucile Packard Fellowship for Science and Engineering
- Basil O'Connor Award, March of Dimes
- John Merck Scholars Award in the Biology of Developmental Disabilities in Children
- Society for Neuroscience
- American Society for Cell Biology
- Genetics Society of America