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

• Published in: Cell reports (Cambridge) Vol. 43; no. 7; p. 114375
• Main Authors: Halim, Dilara O., Krishnan, Gopinath, Hass, Evan P., Lee, Soojin, Verma, Mamta, Almeida, Sandra, Gu, Yuanzheng, Kwon, Deborah Y., Fazzio, Thomas G., Gao, Fen-Biao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2024; Elsevier
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; ASO; C9ORF72; C9orf72 Protein - genetics; C9orf72 Protein - metabolism; CP: Cell biology; CP: Neuroscience; DNA Repeat Expansion - genetics; DPR; exocyst; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; FTD; Humans; Induced Pluripotent Stem Cells - metabolism; iPSC; Motor Neurons - metabolism; Motor Neurons - pathology; neurodegeneration; neuron; poly(GR); CP: Cell biology; CP: Neuroscience; exocyst; DPR; FTD; iPSC; ALS; neurodegeneration; neuron; ASO; C9ORF72; poly(GR)
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114375

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. [Display omitted] •The N-terminal fragment of EXOC2 is sufficient to maintain cell viability•Deletion of EXOC2 in C9ORF72-ALS/FTD motor neurons rescues disease phenotypes•EXOC2 ASOs reduce axon degeneration and apoptosis in C9ORF72 motor neurons•Loss of EXOC2 decreases the levels of DPR proteins and expanded G4C2 repeats RNA Halim et al. deleted the gene EXOC2 from patient stem cells and then differentiated them into motor neurons. They found that several amyotrophic lateral sclerosis-related phenotypes were rescued in patient neurons when EXOC2 was deleted or knocked down by a drug. This study identifies EXOC2 as a potential therapeutic target.