The lesions seen in the degenerating neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) consist primarily of the TDP-43 protein. How aggregated TDP-43 protein causes neuronal dysfunction and neurodegeneration is poorly understood. However, mutations in the gene encoding TDP-43 cause some forms of familial ALS proving that abnormal TDP-43 causes neurodegeneration. Furthermore, TDP-43 positive pathological lesions appear in postmortem samples from several different neurodegenerative disorders including FTLD-U, ALS, Alzheimer's disease (AD), Parkinson's disease, dementia with Lewy bodies, and Guam amyotrophic lateral sclerosis/Parkinson's dementia. To model TDP-43 neurotoxicity in a simple animal model, we have transgenically expressed human TDP-43 protein in the neurons of the nematode worm, C. elegans. Expression of human TDP-43 in worm neurons causes neuronal dysfunction and accumulation of nuclear inclusions consisting of aggregated insoluble TDP-43 protein. We have previously reported a C. elegans model for the tau pathology seen in human tauopathy disorders including and AD. We propose to use the same methodologies to characterize the new model for TDP-43 proteinopathy with a focus on the mechanisms of TDP-43 mediated neurotoxicity and how the localization of TDP-43 protein alters its toxicity. The neuronal consequences of tau and TDP-43 protein expression will be investigated by profiling the transcriptional and post-translational responses to neurotoxicity. Transcriptional changes will be monitored using an mRNA tagging/microarray hybridization approach to identify genes up-regulated and down-regulated in response to neurotoxicity. The, genetic pathways that normally act to protect against the neurotoxic effects of TDP-43 will be identified using a genome-wide RNAi screening approach. Genes normally required for tau neurotoxicity will also be tested for their ability to modify the neurotoxicity of TDP-43. The long term goal of this work is to develop neuroprotective strategies for neurodegenerative disorders with TPD-43 and tau protein deposits.

Public Health Relevance

Deposits of abnormally folded aggregated protein are found in a number of disorders affecting the nervous system including Alzheimer's disease and amyotrophic lateral sclerosis. We have generated different animal models for the nerve cell death seen in these disorders using the worm, C. elegans to understand how protein misfolding can causes disease. Our current work focuses on the newly identified aggregating protein TDP-43, a protein that forms misfolded protein deposits in many different nervous system disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064131-05
Application #
8462699
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2009-05-15
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$252,653
Indirect Cost
$66,468
Name
Seattle Institute for Biomedical/Clinical Research
Department
Type
DUNS #
928470061
City
Seattle
State
WA
Country
United States
Zip Code
98108
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