The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD

Dilara O. Halim; Gopinath Krishnan; Evan P. Hass; Soojin Lee; Mamta Verma; Sandra Almeida; Yuanzheng Gu; Deborah Y. Kwon; Thomas G. Fazzio; Fen-Biao Gao

Cell Reports (Jul 2024)

The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD

Dilara O. Halim,
Gopinath Krishnan,
Evan P. Hass,
Soojin Lee,
Mamta Verma,
Sandra Almeida,
Yuanzheng Gu,
Deborah Y. Kwon,
Thomas G. Fazzio,
Fen-Biao Gao

Affiliations

Dilara O. Halim: Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Gopinath Krishnan: Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Evan P. Hass: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Soojin Lee: Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Mamta Verma: Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Sandra Almeida: Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Yuanzheng Gu: Neuromuscular & Muscle Disorders, Biogen, Cambridge, MA 02142, USA
Deborah Y. Kwon: Neuromuscular & Muscle Disorders, Biogen, Cambridge, MA 02142, USA
Thomas G. Fazzio: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Fen-Biao Gao: Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 7
p. 114375

Abstract

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Summary: GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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