935A Poster - 15. Models of human disease
Thursday April 07, 2:00 PM - 4:00 PM

Authors:
Tyler Fortuna ¹; Sukhleen Kour ¹; Eric Anderson ¹; Caroline Ward ¹; Dhivyaa Rajasundaram ²; Christopher Donnelly ³; Udai Pandey ¹

Affiliations:
1) Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC; 2) Division of Health Informatics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 3) Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Keywords:
a. neural degeneration; b. death mutants/genes

Mutations in Fused in Sarcoma (FUS) have been linked with juvenile and aggressive form of amyotrophic lateral sclerosis (ALS). Cytoplasmic aggregation and defects in DNA repair pathway have been linked with ALS pathogenesis. However, the molecular mechanisms and genetic modifers of DNA damage repair pathway are yet not known. While doing RNA-sequencing analysis of the Drosophila brains expressing FUS, we identified significantly altered genes and pathways involved in FUS-mediated neurodegeneration in vivo. We found that the DEAD-Box Helicase 17 (DDX17) expression level was significantly downregulated in response to mutant FUS in Drosophila and human cell lines. Interestingly, mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and biochemically interacts with DDX17 through the RGG1 domain of FUS. Importantly, genetic upregulation 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.