title: Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress.
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.
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Daejeon 34053, South Korea.
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Jun
authors.affiliation: 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.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Ryu
authors.affiliation: Department of Applied Biology, College of Ecology and Environmental Science, Kyungpook National University, Sangju 37224, South Korea.
authors.forename: Yong-Woo
authors.initials: YW
authors.lastname: Jun
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: Chae-Seok
authors.initials: CS
authors.lastname: Lim
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
authors.affiliation: Department of Applied Biology, College of Ecology and Environmental Science, Kyungpook National University, Sangju 37224, South Korea.
authors.forename: Deok-Jin
authors.initials: DJ
authors.lastname: Jang
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Daejeon 34053, South Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008813:Mice, Inbred ICR; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology; D016501:Neurites / Q000473:pathology*; D018384:Oxidative Stress; D066329:Protein Aggregates; D011485:Protein Binding; D000072417:Protein Domains; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C000599550:FUS protein, human; D050505:Mutant Proteins; D066329:Protein Aggregates; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS; D012097:Repressor Proteins; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases