Fen-Biao Gao, PhD
Department of Neurology
University of Massachusetts Medical School
Albert Sherman Center, Room AS6.1051
368 Plantation Street
Worcester, MA 01605
Faculty page: http://profiles.umassmed.edu/profiles/ProfileDetails.aspx?From=SE&Person=1368
Frontotemporal dementia (FTD) is an age-dependent neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes and recognized now as the most common form of dementia before the age of 60. Unfortunately, the molecular pathogenesis of FTD remains largely unknown and effective treatments are not available. Recent exciting advances indicate that FTD is often associated with amyotrophic lateral sclerosis (ALS) and several genes are involved in thepathogenesis of both FTD and ALS, including CHMP2B, TDP-43, FUS, and C9ORF72. How these mutant proteins cause or contribute to neuronal dysfunction and neurodegenerationin FTD remains poorly defined.
A few years ago, we cloned anovel Drosophila gene calledshrub, which encodes a key component of ESCRT-III and regulates dendritic morphogenesis. In cultured cortical neurons, we found that dysfunctional ESCRT-III, lacking essential components (such as mSnf7-2, one of the mouse homologs of Shrub) or containing ectopically expressed FTD3-associated mutant CHMP2B, causes dendritic retraction,autophagosome accumulation and eventual neurodegeneration. Through an unbiased genetic screen in a Drosophila modelof FTD3, we identified several genetic modifiers of CHMP2B toxicity in vivo that are currently being characterized. We have also been using Drosophila models to study other FTD genes.
We have also established patient-specific induced pluripotent stem cells (iPSC) models of FTD with mutations in progranulin, C9ORF72 and other genes. Over the next a few years, we will use a combination of molecular, cellular, and genetic approaches in both Drosophila and iPSCs models to further dissect the pathogenic mechanisms involving these FTD disease genes. Our ultimate goal is to identify common underlying pathogenic pathways as potential targets for therapeutic interventions.
List of Key papers
Lee A, Li W, Xu K, Bogert BA, Su K, Gao F-B. (2003) Control of dendritic development by the Drosophila fragile X-related gene involves the small GTPase Rac1. Development 130, 5543–5552.
Li W, Gao F-B. (2003) Actin filament–stabilizing protein tropomyosin regulates the size of dendritic fields. J. Neurosci. 23, 6171–6175.
Li W, Wang F, Menut L, Gao F-B. (2004) BTB/POZ-zinc finger protein Abrupt regulates dendritic branching in a neuronal subtype-specific and dosage-dependent manner. Neuron 43, 823–834.
Xu K, Bogert BA, Li W, Su K, Lee A, Gao F-B. (2004) The fragile X-related gene affects the crawling behavior of Drosophila larvae by regulating the mRNA level of the DEG/ENaC subunit Pickpocket1. Curr. Biol. 14, 1025–1034.
Li Y, Wang F, Lee J, Gao F-B. (2006) miRNA-9a ensures the precise specification of neuronal precursors in Drosophila. Genes Dev. 20, 2793–2805.
Sweeney NT, Brenman JE, Jan YN, Gao F-B. (2006) The coiled-coil protein Shrub controls neuronal morphogenesis in Drosophila. Curr. Biol. 16, 1006–1011.
Lee J-A, Beigneux A, Ahmad ST, Young SG, Gao F-B. (2007) ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17, 1561–1567.
Xu, X, Li Y, Wang F, Gao F-B. (2008). The steady-state level of the nervous system-specific microRNA-124a is regulated by dFMR1 in Drosophila. J. Neurosci. 28:11883–11889.
Lee J-A, Gao F-B. (2009) Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia. J. Neurosci. 29, 8506–8511.
Ahmad ST, Sweeney ST, Lee J-A, Sweeney NT, Gao F-B. (2009) A genetic screen identifies Serpin5 as a regulator of the Toll pathway and CHMP2B toxicity associated with frontotemporal dementia. Proc. Nat. Acad. Sci. USA. 106, 12168–12173.
Jiao J, Herl LD, Farese RV Jr, Gao F-B. (2010) MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS ONE 5, e10551.
Delaloy C, Liu L, Lee J-A, Su H, Shen F, Yang GY, Young WL, Ivey KN, Gao F-B. (2010) MicroRNA-9 coordinates proliferation and migration of human embryonic stem cells-derived neural progenitors. Cell Stem Cell 6, 323–335.
Xu XL, Zong R, Li Z, Biswas MH, Fang Z, Nelson DL, Gao F-B. (2011) FXR1P but not FMRP regulates the levels of mammalian brain-specific microRNA-9 and microRNA-124. J. Neurosci. 13:13705–13709.