Frontotemporal dementia (FTD), the second most common form of age-dependent dementia, is associated with focal degeneration of the frontal and temporal lobes. This insidious disorder is distinct from Alzheimer's disease (AD). For instance, recent studies indicate that FTD patients have shorter survival and faster rates of cognitive and functional decline than AD patients, and many lack the pathological hallmarks of AD (Boxer et al., 2005;Neary et al., 2005). On average, FTD strikes patients at 50 to 60 years of age who are still in the work force. Therefore, the disorder represents a serious medical condition and imposes a significant challenge both to affected families and to society. Much remains to be learned about the genetic and molecular mechanisms underlying the pathogenesis of FTD. FTD has a variable clinical presentation that likely involves multiple genetic factors. In some patients, the microtubule-binding protein tau plays a central role in disease progression. However, many FTD patients do not exhibit tauopathies, and so it remains essential to understand other genetic pathways whose defects may contribute to this disorder. Dominant mutations in the CHMP2B gene cause a familial form of FTD linked to chromosome 3 (FTD3). CHMP2B is the human ortholog of the yeast protein Vps2, a key component in ESCRT-III, which is essential for the processing of transmembrane proteins through the endosomal-lysosomal pathway. How these human mutations lead to neurodegeneration remains unclear. Our preliminary results indicate that dysfunction of ESCRT-III leads to neuronal cell death. Here we propose to continue to use an in vitro cellular model and an in vivo fly model of FTD3 to investigate the molecular mechanisms and genetic pathways involved in this neurodegenerative disorder. We will test the hypothesis that FTD3 mutations interfere with the normal function of the ESCRT-III complex in mammalian neurons. We will also investigate the mechanisms of FTD-related neurodegeneration in Drosophila models. Moreover, we will identify and characterize genetic modifiers to provide further mechanistic insights.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057553-05
Application #
7994752
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2007-12-15
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$317,383
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
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Yang, Dejun; Abdallah, Abbas; Li, Zhaodong et al. (2015) FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol 130:525-35
Tran, Helene; Almeida, Sandra; Moore, Jill et al. (2015) Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron 87:1207-1214
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