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
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.
