title: Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1.
abstract: Mutations in the RNA-binding protein FUS/TLS (FUS) have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Although predominantly nuclear, this heterogenous nuclear ribonuclear protein (hnRNP) has multiple functions in RNA processing including intracellular trafficking. In ALS, mutant or wild-type (WT) FUS can form neuronal cytoplasmic inclusions. Asymmetric arginine methylation of FUS by the class 1 arginine methyltransferase, protein arginine methyltransferase 1 (PRMT1), regulates nucleocytoplasmic shuttling of FUS. In motor neurons of primary spinal cord cultures, redistribution of endogenous mouse and that of ectopically expressed WT or mutant human FUS to the cytoplasm led to nuclear depletion of PRMT1, abrogating methylation of its nuclear substrates. Specifically, hypomethylation of arginine 3 of histone 4 resulted in decreased acetylation of lysine 9/14 of histone 3 and transcriptional repression. Distribution of neuronal PRMT1 coincident with FUS also was detected in vivo in the spinal cord of FUS(R495X) transgenic mice. However, nuclear PRMT1 was not stable postmortem obviating meaningful evaluation of ALS autopsy cases. This study provides evidence for loss of PRMT1 function as a consequence of cytoplasmic accumulation of FUS in the pathogenesis of ALS, including changes in the histone code regulating gene transcription.
authors.affiliation: Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Michael
authors.initials: M
authors.lastname: Tibshirani
authors.affiliation: Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Tradewell
authors.affiliation: Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Mattina
authors.affiliation: Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Sandra
authors.initials: S
authors.lastname: Minotti
authors.affiliation: Robarts Research Institute, Western University, London, Ontario, Canada N6A 5C1 and.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Hongru
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Robarts Research Institute, Western University, London, Ontario, Canada N6A 5C1 and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Strong
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Hayward
authors.affiliation: Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4 heather.durham@mcgill.ca.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D019175:DNA Methylation; D004195:Disease Models, Animal; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism
chemical_list: C000599550:FUS protein, human; C000599551:FUS protein, mouse; D006657:Histones; D034702:RNA-Binding Protein FUS; D012097:Repressor Proteins; C099988:PRMT1 protein, human; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases