Neurodegeneration is characterized by the progressive loss of neuron function resulting in physical and cognitive defects that can cause death. Neurodegenerative diseases such as Alzheimer's are a substantial health issue. Currently, there is no effective means to prevent neurodegeneration in any disease. We want to understand the molecular and cellular events that are required for neurodegeneration in a rare disease Ataxia-telangiectasia (A-T), which is caused by mutation of the A- T mutated (ATM) gene. In A-T, neurodegeneration begins before the age of two and worsens with age. We have used Drosophila melanogaster as an experimental model to study A-T. To date, we have found that ATM mutations in neurons disrupt cell cycle regulation, which causes quiescent neurons to reenter the mitotic cell cycle and die. We have also found that ATM mutations in glial cells activate the innate immune response through the NF-?B transcription factor Relish, which causes neurons to die. These findings in flies are relevant to humans. Neuron cell cycle reentry and activation of the innate immune response occur in individuals with A-T as well as in individuals with other neurodegenerative diseases such as Alzheimer's. In the proposed studies, we will continue to use flies because they are the only animal model currently available that undergoes neurodegeneration as a result of ATM mutation. Moreover, the arsenal of molecular and genetic tools available in flies make it possible to rapidly investigate the molecules and pathways that underlie neurodegeneration, providing a framework for developing targeted therapies. To delineate the pathway of events that cause neurodegeneration in A-T we proposed to: (1) determine the factors and signaling events that activate Relish to cause neurodegeneration in ATM mutant flies and (2) determine the transcription targets of Relish at are necessary and sufficient to cause neurodegeneration in ATM mutant flies.

Public Health Relevance

Ataxia-telangiectasia (A-T) is a human neurodegenerative disease. Our studies in fruit flies, Drosophila melanogaster, have uncovered novel pathways of molecular events that cause neurodegeneration in A- T. The proposed research will build upon these findings to accomplish the goal of preventing neurodegeneration in A-T and other diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS083596-01A1
Application #
8688528
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715