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

Sandra Almeida, Eduardo Gascon, Hélène Tran, Hsin Jung Chou, Tania D 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

Research output: Contribution to journalArticle

195 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)385-399
Number of pages15
JournalActa Neuropathologica
Volume126
Issue number3
DOIs
StatePublished - Sep 2013

Fingerprint

Induced Pluripotent Stem Cells
Frontotemporal Dementia
Neurons
Autophagy
Fibroblasts
RNA
Phenotype
Cell Line
RNA-Binding Proteins
Biopsy
Skin
Mutation

Keywords

  • ALS
  • Autophagy
  • C9ORF72
  • FTD
  • Hexanucleotide repeats
  • iPSCs
  • Neurodegeneration
  • Neurons
  • p62
  • RAN translation
  • RNA foci

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. / Almeida, Sandra; Gascon, Eduardo; Tran, Hélène; Chou, Hsin Jung; Gendron, Tania D; Degroot, Steven; Tapper, Andrew R.; Sellier, Chantal; Charlet-Berguerand, Nicolas; Karydas, Anna; Seeley, William W.; Boxer, Adam L.; Petrucelli, Leonard; Miller, Bruce L.; Gao, Fen Biao.

In: Acta Neuropathologica, Vol. 126, No. 3, 09.2013, p. 385-399.

Research output: Contribution to journalArticle

Almeida, S, Gascon, E, Tran, H, Chou, HJ, Gendron, TD, Degroot, S, Tapper, AR, Sellier, C, Charlet-Berguerand, N, Karydas, A, Seeley, WW, Boxer, AL, Petrucelli, L, Miller, BL & Gao, FB 2013, 'Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons', Acta Neuropathologica, vol. 126, no. 3, pp. 385-399. https://doi.org/10.1007/s00401-013-1149-y
Almeida, Sandra ; Gascon, Eduardo ; Tran, Hélène ; Chou, Hsin Jung ; Gendron, Tania D ; Degroot, Steven ; Tapper, Andrew R. ; Sellier, Chantal ; Charlet-Berguerand, Nicolas ; Karydas, Anna ; Seeley, William W. ; Boxer, Adam L. ; Petrucelli, Leonard ; Miller, Bruce L. ; Gao, Fen Biao. / Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. In: Acta Neuropathologica. 2013 ; Vol. 126, No. 3. pp. 385-399.
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AU - Tapper, Andrew R.

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AU - Karydas, Anna

AU - Seeley, William W.

AU - Boxer, Adam L.

AU - Petrucelli, Leonard

AU - Miller, Bruce L.

AU - Gao, Fen Biao

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