title: Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients.
abstract: Mutations in the granulin (GRN) gene cause frontotemporal dementia (FTD) due to progranulin haploinsufficiency. Compounds that can increase progranulin production and secretion may be considered as potential therapeutic drugs; however, very few of them have been directly tested on human cortical neurons. To this end, we differentiated 9 induced pluripotent stem cell lines derived from a control subject, a sporadic FTD case and an FTD patient with progranulin S116X mutation. Treatment with 1 μM suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased the production of progranulin in cortical neurons of all subjects at both the mRNA and protein levels without affecting their viability. Microarray analysis revealed that SAHA treatment not only reversed some gene expression changes caused by progranulin haploinsufficiency but also caused massive alterations in the overall transcriptome. Thus, histone deacetylase inhibitors may be considered as therapeutic drugs for GRN mutation carriers. However, this class of drugs also causes drastic changes in overall gene expression in human cortical neurons and their side effects and potential impacts on other pathways should be carefully evaluated.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.affiliation: Department of Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: fen-biao.gao@umassmed.edu.
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
mesh_terms: D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D057180:Frontotemporal Dementia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D000077153:Progranulins; D000077337:Vorinostat
chemical_list: C492314:GRN protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D000077337:Vorinostat
keywords: Frontotemporal dementia; Microarray; Neurons; Progranulin; SAHA; iPSCs