TDP-43 is a major pathological protein in amyotrophic lateral sclerosis (ALS) and some forms of frontotemporal dementia (FTD) and is also present in ubiquitinated inclusions seen in other neurodegenerative diseases. How TDP-43 contributes to age-dependent neurodegeneration is largely unknown. TDP-43, an evolutionarily highly conserved RNA-binding protein mostly localized to the nucleus, participates in transcriptional repression, alternative splicing, mRNA trafficking, and possibly other aspects of RNA metabolism. However, its functions in postmitotic neurons have not been extensively studied. Normally, TDP-3 has a diffuse nuclear distribution. In diseased neurons, however, TDP-43 and its processed fragments aggregate into cytoplasmic ubiquitinated inclusions. Thus, loss of the normal function ofTDP-43 might contribute to neurodegeneration, perhaps in concert with other mechanisms, such as a toxic gain-of-function for TDP-43 fragments. In this R21 application, we propose to investigate the normal functions of endogenous TDP-43 in postmitotic neurons, which will likely provide important insight into the molecular mechanisms underlying TDP-43-related neurodegeneration.

Public Health Relevance

In this application, we will test the hypothesis that loss of TDP-43 activity affects neuronal structural integrity therefore contributes to eventual neurodegeneration associated with a number of age-dependent neurodegenerative diseases. To this end, we will use fruitfly Drosophila as our primary model system for all the proposed studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS066901-03
Application #
7938604
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2010
Total Cost
$246,750
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Neurology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655