Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes. Recent exciting progress indicates that FTLD and amyotrophic lateral sclerosis (ALS) share pathogenic mechanisms. For instance, TDP-43, an evolutionarily conserved RNA- binding protein mostly localized to the nucleus, is a major pathogenic protein involved in FTLD and ALS, and in other neurodegenerative diseases. However, little is known about how TDP-43 contributes to age-dependent neurodegeneration. TDP-43 contributes to several aspects of RNA metabolism, and disease initiation or progression may involve both loss of the normal function of TDP-43 and toxic gain-of-function mechanisms. To dissect these complex mechanisms in detail, proper in vivo animal models are critically important. We propose to establish novel Drosophila models of TDP-43 toxicity and investigate how disease mutations compromise the function of TDP-43 and lead to neuronal dysfunction in vivo. These studies will likely provide important insights into the molecular pathogenic mechanisms of several neurodegenerative diseases that involve TDP- 43 pathology.

Public Health Relevance

In this proposal, we will establish a novel fly model of neurodegeneration and perform a number of genetic and molecular experiments. These studies will offer novel mechanistic insights into the neurotoxicity of mutant TDP-43, which will likely enhance our understanding of molecular pathogenic mechanisms of frontotemporal dementia and amyotrophic lateral sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS077294-01A1
Application #
8308894
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$205,625
Indirect Cost
$80,625
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