Journal
ACTA NEUROPATHOLOGICA
Volume 142, Issue 3, Pages 515-536Publisher
SPRINGER
DOI: 10.1007/s00401-021-02333-z
Keywords
Neurodegeneration; ALS; FTD; Motor neuron disease; iPSC neurons; Drosophila; DNA-damage repair; FUS; DDX17; RGG-domain
Categories
Funding
- National Institute on Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA) [R01 NS081303, R21 NS094921, R21 NS101661, R21 NS111768, R21 AG064940, R21 NS100055, R01NS105756]
- NIGMS [R35GM119790]
- Muscular Dystrophy Association
- ALS Association
- NOMIS foundation
- Hermann und Lilly Schilling-Stiftung fur medizinische Forschung im Stifterverband
- Robert Packard Center for ALS at Johns Hopkins
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The study found that DDX17 is significantly downregulated in response to ALS caused by FUS mutations, and restoration of DDX17 levels can suppress FUS-mediated neuropathogenesis and toxicity in vivo.
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.
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