DDX17 is involved in DNA damage repair and modifies FUS toxicity in an RGG-domain dependent manner.

Autor: Fortuna TR; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Kour S; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Anderson EN; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Ward C; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Rajasundaram D; Division of Health Informatics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Donnelly CJ; LiveLikeLou Center for ALS Research, Brain Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Hermann A; Translational Neurodegeneration Section 'Albrecht-Kossel', Department of Neurology, University Medical Center, University of Rostock, 18147, Rostock, Germany.; German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, 18147, Rostock, Germany.; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center, University of Rostock, 18147, Rostock, Germany., Wyne H; Department of Biochemistry, Uniformed Services University, Bethesda, MD, USA., Shewmaker F; Department of Biochemistry, Uniformed Services University, Bethesda, MD, USA., Pandey UB; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. udai@pitt.edu.; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. udai@pitt.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2021 Sep; Vol. 142 (3), pp. 515-536. Date of Electronic Publication: 2021 Jun 01.
DOI: 10.1007/s00401-021-02333-z
Abstrakt: Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration. We observed the expression levels of DEAD-Box Helicase 17 (DDX17) to be significantly downregulated in response to mutant FUS in Drosophila and human cell lines. Mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and physically interacts with DDX17 through the RGG1 domain of FUS. Ectopic expression of DDX17 reduces cytoplasmic mislocalization and sequestration of mutant FUS into cytoplasmic stress granules. We identified DDX17 as a novel regulator of the DNA damage response pathway whose upregulation repairs defective DNA damage repair machinery caused by mutant neuronal FUS ALS. In addition, we show DDX17 is a novel modifier of FUS-mediated neurodegeneration in vivo. Our findings indicate DDX17 is downregulated in response to mutant FUS, and restoration of DDX17 levels suppresses FUS-mediated neuropathogenesis and toxicity in vivo.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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