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 Research Focus: Understanding ALS and Frontotemporal Dementia 

Dr. Fen-Biao GaoFen-Biao Gao Lab Website

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 ALS and FTD, including CHMP2B, TDP-43, FUS, TBK1, and C9ORF72. How these mutant proteins cause or contribute to neuronal dysfunction and neurodegeneration in ALS and FTD remains poorly defined.

A few years ago, we cloned anovel Drosophila gene called shrub, 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 ALS/FTD genes, in paticular, C9ORF72.

We have also established patient-specific induced pluripotent stem cells (iPSC) models of FTD and ALS with mutations in progranulin, TDP-43, 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 ALS/FTD disease genes. Our ultimate goal is to identify common underlying pathogenic pathways as potential targets for therapeutic interventions in both ALS and FTD.

Summary Our lab uses a combination of molecular, cellular, genetic, and behavioral approaches to further dissect the pathogenic mechanisms of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis with a focus on mutant CHMP2B, progranulin and C9ORF72. We will identify common underlying pathways as potential targets for therapeutic interventions.
One or more keywords matched the following items that are connected to Gao, Fen-Biao
Item TypeName
Academic Article Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching.
Academic Article Progranulin, a glycoprotein deficient in frontotemporal dementia, is a novel substrate of several protein disulfide isomerase family proteins.
Academic Article Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects.
Academic Article Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons.
Academic Article Syntaxin 13, a genetic modifier of mutant CHMP2B in frontotemporal dementia, is required for autophagosome maturation.
Academic Article ESCRT, autophagy, and frontotemporal dementia.
Academic Article Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia.
Academic Article MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia.
Academic Article Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.
Concept Frontotemporal Dementia
Academic Article Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations.
Academic Article Expression of mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, causes eye deformities due to Notch misregulation in Drosophila.
Academic Article Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency.
Academic Article The emerging roles of microRNAs in the pathogenesis of frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders.
Academic Article Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia.
Academic Article Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia
Academic Article Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia.
Academic Article FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions.
Academic Article Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice.
Academic Article Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients.
Academic Article Lost & found: C9ORF72 and the autophagy pathway in ALS/FTD.
Academic Article Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts.
Academic Article Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability.
Academic Article MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations.
Academic Article Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons.
Academic Article Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients.
Academic Article Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder.
Academic Article Insights into C9ORF72-Related ALS/FTD from Drosophila and iPSC Models.
Academic Article The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia.
Academic Article Partial inhibition of the overactivated Ku80-dependent DNA repair pathway rescues neurodegeneration in C9ORF72-ALS/FTD.
Academic Article C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo.
Academic Article Transcription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD.
Academic Article CRISPR deletion of the C9ORF72 promoter in ALS/FTD patient motor neurons abolishes production of dipeptide repeat proteins and rescues neurodegeneration.
Academic Article Ik2/TBK1 and Hook/Dynein, an adaptor complex for early endosome transport, are genetic modifiers of FTD-associated mutant CHMP2B toxicity in Drosophila.
Academic Article CRISPR-Cas9 Screens Identify the RNA Helicase DDX3X as a Repressor of C9ORF72 (GGGGCC)n Repeat-Associated Non-AUG Translation.
Academic Article Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD.
Academic Article TBK1 haploinsufficiency in ALS and FTD compromises membrane trafficking.
Academic Article Translation of the poly(GR) frame in C9ORF72-ALS/FTD is regulated by cis-elements involved in alternative splicing.
Academic Article Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM.
Academic Article Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD.
Search Criteria
  • Frontotemporal Dementia