Examining regulation of tau protein

George Jackson, MD, PhD
University of Texas Medical Branch (Galveston, TX )
Year Awarded:
2007
Grant Duration:
April 1, 2007 to August 31, 2010
Disease:
Alzheimer's Disease
Award Amount:
$400,000
Grant Reference ID:
A2007168
Award Type:
Standard
Award Region:
US Southern
In memory of Marion Ahlstrom Hoffman

Validation and Characterization of Tau Modifiers In Vivo

Summary

These experiments propose further studies of the role of PSA in tauopathy, and plan to validate other genes identified as putative protective or susceptibility genes in the transgenic human tau P301L mouse model.

Details

Neurofibrillary tangles containing tau are a hallmark of Alzheimer's disease. However, little is known about ways to protect brain cells from degeneration caused by tau. We looked at gene expression in several parts of the brain of mice expressing human tau including a mutation that causes FTD. This was done in combination with testing in the simple fruit fly. We identified several novel modifiers of tau neurotoxicity including the highly conserved protein, puromycin-sensitive aminopeptidase (PSA). Here, we propose further studies of the role of PSA in tauopathy, and plan to validate other genes identified as putative protective or susceptibility genes in the transgenic human tau P301L mouse model. These will involve crossing fruit flies that express tau with other lines that have greater and/or lesser expression of the genes identified in the mouse. Genes that succeed in changing tau toxicity can easily be identified under the microscope by examining the size of the fly eye. Validation and characterization of mechanisms of action of tau modifiers using the fly model will provide a first step toward identifying those modifiers which are most promising as therapeutic targets for AD; these may then be further studied in cell culture and mice.

Publications

Ratnaparkhi A, Lawless GM, Schweizer FE, Golshani P, Jackson GR (2008) A Drosophila Model of ALS: Human ALS-Associated Mutation in VAP33A Suggests a Dominant Negative Mechanism. PLoS ONE 3(6): e2334.

Chatterjee, S., Sang, T.K., Lawless, G.M. and Jackson, G.R. (2009) Dissociation of tau toxicity and phosphorylation: Role of GSK-3â, MARK, and Cdk5 in a Drosophila model. Hum. Mol. Genet. 18, 164-177. PubMed Icon Google Scholar Icon

Ambegaokar, S.S. and Jackson, G.R. (2010) Interaction between eye pigment genes and tau-induced neurodegeneration in a Drosophila melanogaster model of tauopathy. Genetics 186, 435-442. PubMed Icon Google Scholar Icon

Ambegaokar, S.S. and Jackson, G.R. (2011) Double vision: Pigment genes do more than just color. Fly 5, 206-209. PubMed Icon Google Scholar Icon

Ambegaokar, S.S. and Jackson, G.R. (2011) Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation. Hum. Mol. Genet. epub ahead of print Sept. 23. [PMID: nd]

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