Many human neurodegenerative diseases are poorly understood as well as untreatable, including Parkinson's, Alzheimer's and Huntington's diseases. For some familial forms of these diseases, mutations in specific genes products associated with disease are known, allowing the possibility to model the disease in simple systems in order to address mechanisms of degeneration and to pioneer novel treatments. Toward this end, we applied a new approach to the problem of polyglutamine-induced neurodegeneration by developing a model for this class of human disease in the fruit fly Drosophila melanogaster. These experiments demonstrated that fundamental molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila, such that Drosophila genetics can be applied to investigate these human diseases in order to address mechanisms of degeneration and define new means of treatment. Using this model, we have shown that the molecular chaperones, which are highly conserved proteins, are potent modulators of neurodegeneration in vivo. We now propose to apply the powerful molecular genetics of Drosophila in genetic screens to uncover additional modulators of neurodegeneration. The advantage of genetic screens is that they provide the ability to define genes that can influence and modulate pathogenesis without requiring previous knowledge of the mechanisms involved.
The specific aims are to define novel modulators of neurodegeneration in mis-expression and loss-of-function genetic screens, and to molecularly define and biologically characterize these modifiers in order to address their molecular and biological modes of action. By applying the power of Drosophila molecular genetics to address conserved features of polyglutamine-induced degeneration, these studies provide the foundation for new approaches to cures and treatments for human neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043578-05
Application #
7244234
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Sutherland, Margaret L
Project Start
2003-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$244,798
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Liu, Nan; Landreh, Michael; Cao, Kajia et al. (2012) The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 482:519-23
Bonini, Nancy M; Gitler, Aaron D (2011) Model organisms reveal insight into human neurodegenerative disease: ataxin-2 intermediate-length polyglutamine expansions are a risk factor for ALS. J Mol Neurosci 45:676-83
Shieh, Shin-Yi; Bonini, Nancy M (2011) Genes and pathways affected by CAG-repeat RNA-based toxicity in Drosophila. Hum Mol Genet 20:4810-21
Jung, Joonil; van Jaarsveld, Marijn T M; Shieh, Shin-Yi et al. (2011) Defining genetic factors that modulate intergenerational CAG repeat instability in Drosophila melanogaster. Genetics 187:61-71
Liu, Nan; Abe, Masashi; Sabin, Leah R et al. (2011) The exoribonuclease Nibbler controls 3' end processing of microRNAs in Drosophila. Curr Biol 21:1888-93
Hao, Ling-Yang; Giasson, Benoit I; Bonini, Nancy M (2010) DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function. Proc Natl Acad Sci U S A 107:9747-52
Jung, Joonil; Xu, Kexiang; Lessing, Derek et al. (2009) Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet 18:4843-52
Lessing, Derek; Bonini, Nancy M (2009) Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants. Nat Rev Genet 10:359-70
Li, Ling-Bo; Yu, Zhenming; Teng, Xiuyin et al. (2008) RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453:1107-11
Warrick, John M; Morabito, Lance M; Bilen, Julide et al. (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell 18:37-48