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SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated

Guillaume M Hautbergue1, Lydia M Castelli1, Laura Ferraiuolo1

  • 1Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK.

Nature Communications
|July 6, 2017
PubMed

Insights

Scientists discovered that blocking SRSF1, a nuclear export adaptor, prevents neurodegeneration in C9ORF72-related diseases. This finding offers a promising therapeutic target for neuroprotection against these devastating conditions.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Hexanucleotide repeat expansions in the C9ORF72 gene are the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • Pathological C9ORF72 repeat transcripts and resulting dipeptide repeat proteins induce neurotoxicity through various mechanisms.
  • The nuclear export pathway for these toxic C9ORF72 repeat transcripts remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of nuclear export adaptors in the pathogenesis of C9ORF72-related neurodegenerative diseases.
  • To identify potential therapeutic targets for preventing neurodegeneration caused by C9ORF72 mutations.

Main Methods:

  • Utilized a Drosophila model of C9ORF72-related disease to assess the impact of SRSF1 depletion on neurodegeneration and motor deficits.
  • Conducted co-culture assays with patient-derived motor neurons and astrocytes to evaluate neurotoxicity.
  • Examined the interaction between SRSF1 and NXF1 and its effect on C9ORF72 transcript nuclear export and dipeptide-repeat protein production in various neuronal models.

Main Results:

  • Depletion of SRSF1 significantly ameliorated neurodegeneration and locomotor impairments in the Drosophila model.
  • Intervention targeting SRSF1 reduced cell death in patient-derived motor neurons and mitigated astrocytic-mediated neurotoxicity.
  • Inhibition of SRSF1 or its interaction with NXF1 specifically blocked the nuclear export of pathogenic C9ORF72 transcripts, reduced dipeptide-repeat protein synthesis, and alleviated neurotoxicity across multiple models.

Conclusions:

  • SRSF1 acts as a crucial mediator for the nuclear export of C9ORF72 transcripts containing expanded hexanucleotide repeats.
  • The pathological RNA sequestration of SRSF1 facilitates NXF1-dependent nuclear export, contributing to neurotoxicity.
  • Targeting the SRSF1-NXF1 interaction presents a novel and promising therapeutic strategy for neuroprotection in C9ORF72-related disorders.

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