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Related Experiment Video

Updated: Jun 14, 2025

Assay to Measure Nucleocytoplasmic Transport in Real Time within Motor Neuron-like NSC-34 Cells
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C9orf72 polyPR interaction with the nuclear pore complex.

Hamidreza Jafarinia1, Erik Van der Giessen1, Patrick R Onck1

  • 1Zernike Institute for Advanced Materials, University of Groningen, Groningen, the Netherlands.

Biophysical Journal
|August 29, 2024
PubMed
Summary
This summary is machine-generated.

Poly-proline-arginine (PR), toxic in ALS/FTD, does not aggregate in the nuclear pore complex (NPC). Instead, PR translocates through the NPC, with translocation difficulty increasing with PR length.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biophysics

Background:

  • The C9orf72 gene mutation is a leading cause of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD).
  • This mutation produces toxic dipeptide repeat proteins, including poly-proline-arginine (polyPR), implicated in cellular dysfunction.
  • PolyPR is hypothesized to disrupt nucleocytoplasmic transport (NCT) by interfering with the nuclear pore complex (NPC).

Purpose of the Study:

  • To investigate the molecular mechanisms of polyPR interaction with the NPC.
  • To elucidate how polyPR affects nucleocytoplasmic transport (NCT).
  • To understand the role of the NPC in polyPR-mediated cellular defects.

Main Methods:

  • Coarse-grained molecular dynamics simulations were employed.
  • Models of polyPR and the yeast NPC, including FG-nucleoporins (FG-Nups), were utilized.
  • Interactions and translocation pathways of polyPR within the NPC were analyzed.

Main Results:

  • PolyPR does not aggregate within the NPC or bind permanently to FG-Nups.
  • PolyPR translocates through the central, low-density region of the NPC.
  • Translocation faces higher energy barriers and narrower channels for longer polyPR chains.
  • Steric interactions dominate between polyPR and FG-Nups, with minor contributions from other forces.

Conclusions:

  • PolyPR traverses the NPC rather than accumulating within it.
  • The size of polyPR influences its translocation efficiency and energy requirements.
  • These findings provide insights into the molecular basis of polyPR-induced NCT disruption in ALS/FTD.