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Open Access 01-09-2013 | Original Paper

Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons

Authors: Sandra Almeida, Eduardo Gascon, Hélène Tran, Hsin Jung Chou, Tania F. Gendron, Steven DeGroot, Andrew R. Tapper, Chantal Sellier, Nicolas Charlet-Berguerand, Anna Karydas, William W. Seeley, Adam L. Boxer, Leonard Petrucelli, Bruce L. Miller, Fen-Biao Gao

Published in: Acta Neuropathologica | Issue 3/2013

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.

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Title: Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons
Authors: Sandra Almeida
Eduardo Gascon
Hélène Tran
Hsin Jung Chou
Tania F. Gendron
Steven DeGroot
Andrew R. Tapper
Chantal Sellier
Nicolas Charlet-Berguerand
Anna Karydas
William W. Seeley
Adam L. Boxer
Leonard Petrucelli
Bruce L. Miller
Fen-Biao Gao
Publication date: 01-09-2013
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-013-1149-y

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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