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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Gascon, Eduardo; Gao, Fen-Biao (2014) The emerging roles of microRNAs in the pathogenesis of frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders. J Neurogenet 28:30-40
Lee, Wing C; Almeida, Sandra; Prudencio, Mercedes et al. (2014) Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. Hum Mol Genet 23:1467-78
Gao, Fen-Biao; Taylor, J Paul (2014) RNA metabolism in neurological disease. Brain Res 1584:1-2
Gascon, Eduardo; Lynch, Kelleen; Ruan, Hongyu et al. (2014) Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia. Nat Med 20:1444-51
Cheruiyot, Abigael; Lee, Jin-A; Gao, Fen-Biao et al. (2014) Expression of mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, causes eye deformities due to Notch misregulation in Drosophila. FASEB J 28:667-75
Almeida, Sandra; Gascon, Eduardo; Tran, Helene et al. (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 126:385-99
Zhang, Zhijun; Almeida, Sandra; Lu, Yubing et al. (2013) Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS One 8:e76055
Lu, Yubing; Zhang, Zhijun; Sun, Danqiong et al. (2013) Syntaxin 13, a genetic modifier of mutant CHMP2B in frontotemporal dementia, is required for autophagosome maturation. Mol Cell 52:264-71
Li, Zhaodong; Lu, Yubing; Xu, Xia-Lian et al. (2013) The FTD/ALS-associated RNA-binding protein TDP-43 regulates the robustness of neuronal specification through microRNA-9a in Drosophila. Hum Mol Genet 22:218-25
Lee, Jin-A; Liu, Lei; Javier, Robyn et al. (2011) ESCRT-III subunits Snf7-1 and Snf7-2 differentially regulate transmembrane cargos in hESC-derived human neurons. Mol Brain 4:37

Showing the most recent 10 out of 12 publications