Mutations in the microtubule-associated protein tau occur in some cases of inherited frontotemporal dementia (FTD), demonstrating that tau abnormalities can cause neurodegeneration. Many FTD mutations occur in regulatory elements that alter splicing and thereby expression of tau isoforms, rather than tau coding sequence. One of the hallmark neuropathologic features of Alzheimer's disease (AD) is the neurofibrillary tangle (NFT), which contains hyperphosphorylated tau. Characterization of the events that modify tau-associated neurodegenerative processes is critical for understanding the pathophysiology of AD, as well as FTD and related diseases, such as progressive supranuclear palsy and corticobasal degeneration, and for the development of therapeutics. In order to test the hypothesis that neurodegeneration can be caused by aberrant expression of wild-type tau, the longest isoform of human tau was overexpressed in the fruit fly, producing degeneration of the eye and underlying brain, but failing to produce neurofibrillary tangles. However, tau phosphorylation by co-expression of shaggy, the Drosophila homologue of glycogen synthase kinase (GSK)-3beta, an important tau kinase in vitro, produced a more severely degenerated eye, as well as lesions resembling NFT (Jackson, G.R., et al. (2002): Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34: 509-519). Here, we will examine whether Shaggy is incorporated into NFT-like lesions in double tau + Shaggy transgenics. We will examine the role of puromycin-sensitive aminopeptidase, which was identified in a pilot screen, as a tau modifier. Finally, we will perform loss of function and gain of function genetic screens in order to identify novel modifiers of the abnormal Drosophila phenotype associated with expression of hyperphosphorylated tau. Modifier genes will be characterized and evaluated as targets for the development of new therapies aimed at alleviating neurofibrillary pathology and neuronal cell death in AD and other neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046489-02
Application #
6919824
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Murphy, Diane
Project Start
2004-07-15
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$357,281
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ambegaokar, Suren S; Jackson, George R (2012) The downward spiral of tau and autolysosomes: a new hypothesis in neurodegeneration. Autophagy 8:1144-5
Klionsky, Daniel J (see original citation for additional authors) (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544
Ambegaokar, Surendra S; Jackson, George R (2011) Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation. Hum Mol Genet 20:4947-77
Ambegaokar, Surendra S; Roy, Bidisha; Jackson, George R (2010) Neurodegenerative models in Drosophila: polyglutamine disorders, Parkinson disease, and amyotrophic lateral sclerosis. Neurobiol Dis 40:29-39
Ambegaokar, Surendra S; Jackson, George R (2010) Interaction between eye pigment genes and tau-induced neurodegeneration in Drosophila melanogaster. Genetics 186:435-42
Chatterjee, Shreyasi; Sang, Tzu-Kang; Lawless, George M et al. (2009) Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model. Hum Mol Genet 18:164-77
Kuo, Sheng-Han; Jackson, George R (2009) Emerging subspecialties in neurology: translational research in movement disorders. Neurology 73:e40-1
Ratnaparkhi, Anuradha; Lawless, George M; Schweizer, Felix E et al. (2008) A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS One 3:e2334
Sang, Tzu-Kang; Chang, Hui-Yun; Lawless, George M et al. (2007) A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J Neurosci 27:981-92
Doglio, Laura E; Kanwar, Ritu; Jackson, George R et al. (2006) gamma-cleavage-independent functions of presenilin, nicastrin, and Aph-1 regulate cell-junction organization and prevent tau toxicity in vivo. Neuron 50:359-75

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