title: Activity-dependent FUS dysregulation disrupts synaptic homeostasis.
abstract: The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS(WT)) and a pathological mutation (FUS(R521G)). FUS(WT) and FUS(R521G) mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUS(R521G) mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUS(R521G) mice show dendritic defects; FUS(WT) mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUS(WT) protein levels but decreases the FUS(R521G) protein, providing a potential biochemical basis for the dendritic spine differences between FUS(WT) and FUS(R521G) mice.
authors.affiliation: Departments of Neuroscience and Institut Universitaire en Santé Mentale de Québec, Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC, Canada G1J 2G3; Chantelle.Sephton.1@ulaval.ca Gang.Yu@UTSouthwestern.edu.
authors.forename: Chantelle F
authors.initials: CF
authors.lastname: Sephton
authors.affiliation: Department of Pediatric Neuropathology and Developmental Neurobiology, University of California, San Francisco, CA 94143;
authors.forename: Amy A
authors.initials: AA
authors.lastname: Tang
authors.affiliation: Departments of Neuroscience and Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75080; and.
authors.forename: Ashwinikumar
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Departments of Neuroscience and.
authors.forename: James
authors.initials: J
authors.lastname: West
authors.affiliation: Departments of Neuroscience and.
authors.forename: Mieu
authors.initials: M
authors.lastname: Brooks
authors.affiliation: Departments of Neuroscience and.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Stubblefield
authors.affiliation: Departments of Neuroscience and.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75080; and Center for Synthetic and System Biology, Tsinghua National Laboratory of Information Science and Technology, Tsinghua University, Beijing 100084, China.
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Zhang
authors.affiliation: Departments of Neuroscience and.
authors.forename: Carla B
authors.initials: CB
authors.lastname: Green
authors.affiliation: Departments of Neuroscience and.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
authors.affiliation: Department of Pediatric Neuropathology and Developmental Neurobiology, University of California, San Francisco, CA 94143;
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Departments of Neuroscience and Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390;
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Departments of Neuroscience and Chantelle.Sephton.1@ulaval.ca Gang.Yu@UTSouthwestern.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003712:Dendrites / Q000235:genetics / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D020125:Mutation, Missense; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D013131:Spine / Q000378:metabolism / Q000473:pathology
chemical_list: D034702:RNA-Binding Protein FUS
keywords: FUS; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; metabotropic glutamate receptors; synaptic homeostasis