Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress

Sci Rep. 2017 Jan 17;7:40474. doi: 10.1038/srep40474.

Abstract

Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L overexpression rescued neurite shortening caused by FUS-R521C upon oxidative stress, while loss of Nd1-L further exacerbated neurite shortening. Altogether, these data suggest that the abnormal stable complex of FUS-R521C/PRMT1/Nd1-L mRNA could contribute to neurodegeneration upon oxidative stress. Overall, our study provides a novel pathogenic mechanism of the FUS mutation associated with abnormal protein-RNA complexes upon oxidative stress in ALS and provides insight into possible therapeutic targets for this pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Cytosol / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Mice, Inbred ICR
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • NADH Dehydrogenase / genetics*
  • NADH Dehydrogenase / metabolism
  • Nerve Degeneration / pathology
  • Neurites / pathology*
  • Oxidative Stress*
  • Protein Aggregates*
  • Protein Binding
  • Protein Domains
  • Protein-Arginine N-Methyltransferases / metabolism*
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Protein FUS / chemistry
  • RNA-Binding Protein FUS / genetics*
  • Repressor Proteins / metabolism*

Substances

  • FUS protein, human
  • Mutant Proteins
  • Protein Aggregates
  • RNA, Messenger
  • RNA-Binding Protein FUS
  • Repressor Proteins
  • NADH Dehydrogenase
  • NADH dehydrogenase subunit 1, human
  • PRMT1 protein, human
  • Protein-Arginine N-Methyltransferases