The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. The simple genetic model of tauopathy in Drosophila melanogaster recapitulates many key features of these diseases, including progressive neurodegeneration and aberrant tau phosphorylation. Furthermore, oxidative stress and cell cycle activation in post- mitotic neurons are key mediators of tau-induced neurodegeneration in humans and Drosophila models of tauopathy. Genetic, biochemical, and neuropathological techniques will be used to investigate the role of tau in the control of chromatin structure and determine the influence of chromatin changes on neurodegeneration. The proposed experiments will identify the types of histone modifications and chromatin complexes that occur due to tau expression in Drosophila. If we produce compelling evidence that tau mediates neurotoxicity through global chromatin alterations, our work will provide significant insight into the pathogenesis of tauopathies, including AD, and will suggest new therapeutic strategies for the disorders

Public Health Relevance

The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. We propose to study tau-induced chromatin alterations in a Drosophila melanogaster model of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AG039193-03
Application #
8319393
Study Section
Special Emphasis Panel (ZRG1-F03A-F (20))
Program Officer
Miller, Marilyn
Project Start
2010-09-30
Project End
2013-09-29
Budget Start
2012-09-30
Budget End
2013-09-29
Support Year
3
Fiscal Year
2012
Total Cost
$53,942
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Frost, Bess; Hemberg, Martin; Lewis, Jada et al. (2014) Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci 17:357-66