UMMS Affiliation

Department of Neurology

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Nervous System Diseases | Neurology | Neuroscience and Neurobiology | Nucleic Acids, Nucleotides, and Nucleosides


GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Brain tissues from affected individuals show characteristic nuclear RNA foci containing the expanded repeat RNAs, as well as neuronal inclusions containing dipeptide repeat (DPR) proteins [poly(GA), poly(GP), poly(GR), poly(PR), and poly(PA)] resulting from the translation of both sense and antisense repeat RNAs in all reading frames. Although reduced C9ORF72 protein function may contribute to disease, the more likely drivers of disease are mechanisms related to a gain of toxic function. Currently, intense efforts are being made to identify disease mechanisms amenable for the development of therapeutic strategies. One promising avenue would be to prevent the production of the expanded repeat RNAs, such as by antisense oligonucleotides. Here, we tested another potential therapeutic approach: CRISPR/Cas9-based targeting of the promoter region.


C9ORF72, amyotrophic lateral sclerosis, ALS, frontotemporal dementia

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Copyright © The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.

DOI of Published Version



Krishnan G, Zhang Y, Gu Y, Kankel MW, Gao FB, Almeida S. CRISPR deletion of the C9ORF72 promoter in ALS/FTD patient motor neurons abolishes production of dipeptide repeat proteins and rescues neurodegeneration. Acta Neuropathol. 2020 Jul;140(1):81-84. doi: 10.1007/s00401-020-02154-6. Epub 2020 Apr 7. PMID: 32266467; PMCID: PMC7300081. Link to article on publisher's site

Journal/Book/Conference Title

Acta neuropathologica

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.