Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72.

Autor: Chai N; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA., Haney MS; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Couthouis J; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Morgens DW; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Benjamin A; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Wu K; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA., Ousey J; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Fang S; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Finer S; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Bassik MC; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Gitler AD; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: agitler@stanford.edu.
Jazyk: angličtina
Zdroj: Brain research [Brain Res] 2020 Feb 01; Vol. 1728, pp. 146601. Date of Electronic Publication: 2019 Dec 13.
DOI: 10.1016/j.brainres.2019.146601
Abstrakt: Mutations in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis (ALS). Both toxic gain of function and loss of function pathogenic mechanisms have been proposed. Accruing evidence from mouse knockout studies point to a role for C9ORF72 as a regulator of immune function. To provide further insight into its cellular function, we performed a genome-wide synthetic lethal CRISPR screen in human myeloid cells lacking C9ORF72. We discovered a strong synthetic lethal genetic interaction between C9ORF72 and FIS1, which encodes a mitochondrial membrane protein involved in mitochondrial fission and mitophagy. Mass spectrometry experiments revealed that in C9ORF72 knockout cells, FIS1 strongly bound to a class of immune regulators that activate the receptor for advanced glycation end (RAGE) products and trigger inflammatory cascades. These findings present a novel genetic interactor for C9ORF72 and suggest a compensatory role for FIS1 in suppressing inflammatory signaling in the absence of C9ORF72.
(Copyright © 2019 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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