Alzheimer's disease is the most common neurodegenerative disease. Pathologically, Alzheimer's disease is characterized by neuronal loss in the context of amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed of a small peptide, Abeta, which is formed from a larger precursor protein (APP). Neurofibrillary tangles are formed from abnormally phosphorylated and aggregated tau protein. Genetic evidence implicates abnormalities in APP processing in familial Alzheimer's disease. Mutations in the tau gene cause frontotemporal dementia. Despite identification of these critical genetic linkages, we still know very little about the molecular and biochemical events mediating neuronal dysfunction and death in Alzheimer's disease and frontotemporal dementia. To enable a comprehensive genetic analysis of these disorders, we have developed genetic models in Drosophila melanogaster. Expression of wild type and mutant human tau in transgenic flies truncates life span, and produces adult onset neurodegeneration associated with abnormally phosphorylated tau. These features replicate key manifestations of human neurodegenerative diseases associated with abnormal tau deposition. We now propose to exploit the genetic potential of the system by generating second site suppressors and enhancers of tau-induced neurodegeneration. Existing collections of well-defined mutant chromosomes will be assayed for their ability to alter the neurodegeneration. De novo mutations will also be generated and tested. Modifiers of neurodegeneration will be characterized molecularly. Mammalian homologues of these Drosophila modifiers will be human disease gene candidates and likely components of mammalian neurodegenerative pathways. We will also test the role of candidate modifiers, including chaperones and the ubiquitination/proteosome pathway in tau-induced neurodegeneration. In addition, we have created a genetic system for studying APP processing. The extracellular and transmembrane regions of APP were fused to green fluorescent protein (GFP) and a nuclear localization signal. Transgenic flies were created that show presenilin dependent nuclear localization of GFP. We will use our easily monitored, presenilin dependent cleavage assay to identify new proteins required for APP processing. These novel modifiers will represent candidate members of the presenilin complex, as well as upstream regulatory factors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG019790-01
Application #
6364344
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Miller, Marilyn
Project Start
2001-09-15
Project End
2006-08-31
Budget Start
2001-09-15
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$308,760
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Loewen, Carin A; Feany, Mel B (2010) The unfolded protein response protects from tau neurotoxicity in vivo. PLoS One 5:
Khurana, Vikram; Elson-Schwab, Ilan; Fulga, Tudor A et al. (2010) Lysosomal dysfunction promotes cleavage and neurotoxicity of tau in vivo. PLoS Genet 6:e1001026
Colodner, Kenneth J; Feany, Mel B (2010) Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy. J Neurosci 30:16102-13
Steinhilb, Michelle L; Dias-Santagata, Dora; Fulga, Tudor A et al. (2007) Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol Biol Cell 18:5060-8
Khurana, Vikram; Feany, Mel B (2007) Connecting cell-cycle activation to neurodegeneration in Drosophila. Biochim Biophys Acta 1772:446-56
Fulga, Tudor A; Elson-Schwab, Ilan; Khurana, Vikram et al. (2007) Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol 9:139-48
Steinhilb, Michelle L; Dias-Santagata, Dora; Mulkearns, Erin E et al. (2007) S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila. J Neurosci Res 85:1271-8
Dias-Santagata, Dora; Fulga, Tudor A; Duttaroy, Atanu et al. (2007) Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 117:236-45
Khurana, Vikram; Lu, Yiran; Steinhilb, Michelle L et al. (2006) TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol 16:230-41

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