title: Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons.
abstract: The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had >1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gascon
authors.forename: Hélène
authors.initials: H
authors.lastname: Tran
authors.forename: Hsin Jung
authors.initials: HJ
authors.lastname: Chou
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Steven
authors.initials: S
authors.lastname: Degroot
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000073885:C9orf72 Protein; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D042622:DNA Repeat Expansion / Q000235:genetics* / Q000502:physiology; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins