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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Mutations in Fused in Sarcoma (FUS) are a primary cause of amyotrophic lateral sclerosis (ALS).
• Cytoplasmic aggregation of mutant FUS and impaired DNA repair are linked to ALS pathogenesis.
• The precise mechanisms of mutant FUS-induced neurodegeneration remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms underlying FUS-mediated neurodegeneration using RNA-sequencing in Drosophila.
• To identify genes and pathways affected by mutant FUS expression.
• To explore the role of DEAD-Box Helicase 17 (DDX17) in FUS-associated ALS.

Main Methods:

• RNA-sequencing in Drosophila brains expressing mutant FUS.
• Analysis of DDX17 expression in Drosophila and human cell lines.
• Investigating the interaction between mutant FUS and DDX17.
• Assessing the impact of DDX17 restoration on FUS-mediated neurodegeneration in vivo.

Main Results:

• Mutant FUS significantly downregulates DDX17 expression in Drosophila and human cells.
• Mutant FUS sequesters nuclear DDX17 into cytoplasmic stress granules and interacts with it via its RGG1 domain.
• Ectopic DDX17 expression reduces mutant FUS cytoplasmic mislocalization.
• DDX17 upregulation repairs DNA damage response defects caused by mutant FUS.
• DDX17 acts as a novel modifier of FUS-mediated neurodegeneration in vivo.

Conclusions:

• DDX17 is downregulated by mutant FUS, contributing to FUS-ALS pathogenesis.
• DDX17 is a novel regulator of DNA damage response and a suppressor of FUS-mediated neurotoxicity.
• Restoring DDX17 levels offers a potential therapeutic strategy for FUS-ALS by mitigating neuropathogenesis.