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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.

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


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.

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