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ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules

Caroline Vance1, Emma L Scotter, Agnes L Nishimura

  • 1Department of Clinical Neuroscience, King’s College London, UK.

Human Molecular Genetics
|March 12, 2013
PubMed

Insights

Mutations in the Fused in Sarcoma (FUS) gene cause amyotrophic lateral sclerosis (ALS). C-terminal mutations cause FUS to mislocalize to the cytoplasm, and cellular stress leads to FUS aggregation, driving neurodegeneration.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease.
  • Mutations in the Fused in Sarcoma (FUS) gene are linked to ALS.
  • FUS protein is crucial for RNA processing and typically resides in the cell nucleus.

Purpose of the Study:

  • To investigate the impact of C-terminal ALS mutations on FUS protein localization and behavior.
  • To elucidate the mechanisms underlying FUS aggregation in ALS pathogenesis.
  • To explore the role of cellular stress in FUS-related neurodegeneration.

Main Methods:

  • Transfection of cells with FUS constructs.
  • Analysis of FUS localization in patient-derived fibroblasts.
  • Induction of oxidative stress.
  • Assessment of FUS protein-protein and RNA-dependent interactions.

Main Results:

  • C-terminal ALS mutations disrupt the nuclear localization signal (NLS) of FUS, causing its accumulation in the cytoplasm.
  • Cytoplasmic FUS mislocalization can be rescued by restoring the wild-type NLS.
  • Oxidative stress recruits mutant FUS to cytoplasmic stress granules, where it can sequester wild-type FUS in an RNA-dependent manner.

Conclusions:

  • A two-hit hypothesis is proposed: cytoplasmic mislocalization of FUS, followed by cellular stress, promotes the formation of toxic cytoplasmic aggregates.
  • These aggregates may sequester FUS, disrupt RNA processing, and initiate motor neuron degeneration in ALS.
  • Understanding FUS mislocalization and aggregation is critical for developing ALS therapies.

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