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Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalization in ALS motor neurons and is

Oliver J Ziff1, Jasmine Harley2, Yiran Wang3

  • 1The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK; National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, WC1N 3BG London, UK.

Neuron
|July 22, 2023
PubMed

Insights

Amyotrophic lateral sclerosis (ALS) involves mislocalized proteins and RNA in motor neurons. Inhibiting VCP ATPase with ML240 partially restored normal localization, suggesting a potential therapeutic strategy for ALS.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) is linked to the mislocalization of TDP-43, an RNA-binding protein (RBP), between the nucleus and cytoplasm.
  • Evidence suggests broader mRNA and protein mislocalization occurs in ALS pathogenesis.

Purpose of the Study:

  • To investigate mRNA and protein localization in induced pluripotent stem cell-derived motor neurons (iPSMNs) from ALS patients with TARDBP and VCP mutations.
  • To explore the relationship between RBP mislocalization and mRNA redistribution in ALS.
  • To assess the therapeutic potential of VCP ATPase inhibition.

Main Methods:

  • Nucleocytoplasmic fractionation, RNA sequencing, and mass spectrometry were used to analyze mRNA and protein localization.
  • iPSMNs derived from ALS patients with TARDBP and VCP mutations were utilized.
  • Treatment with ML240, a VCP ATPase inhibitor, was applied to ALS mutant iPSMNs.

Main Results:

  • ALS mutant iPSMNs showed significant nucleocytoplasmic mRNA redistribution, RBP mislocalization, and altered splicing.
  • Mislocalized proteins demonstrated increased binding affinity to redistributed transcripts, indicating a connection between RBP and mRNA mislocalization.
  • ML240 treatment partially corrected mRNA and protein localization, altered the VCP interactome and lysosomal localization, and reduced oxidative stress and DNA damage.

Conclusions:

  • A strong link exists between RBP mislocalization and mRNA redistribution in ALS motor neurons.
  • VCP ATPase inhibition represents a promising therapeutic avenue for ALS treatment.
Keywords:
RNA binding proteinsVCP inhibitionamyotrophic lateral sclerosismRNA redistributionmotor neuronneurodegenerationnucleocytoplasmic transportprotein mislocalization

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