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

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

Author information

1
Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Daejeon 34053, South Korea.
2
Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea.
3
Department of Life Science, Chung-Ang University, Seoul, 06974, South Korea.
4
Department of Applied Biology, College of Ecology and Environmental Science, Kyungpook National University, Sangju 37224, South Korea.
5
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
6
Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea.

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.

PMID:
28094300
PMCID:
PMC5240339
DOI:
10.1038/srep40474
[Indexed for MEDLINE]
Free PMC Article

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