title: Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2.
abstract: Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2(P497H) transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including Ub(G76V)-GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences.
authors.forename: George H
authors.initials: GH
authors.lastname: Gorrie
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Interdepartmental Neuroscience Program.
authors.forename: Faisal
authors.initials: F
authors.lastname: Fecto
authors.affiliation: Department of Physiology.
authors.forename: Daniel
authors.initials: D
authors.lastname: Radzicki
authors.affiliation: Department of Physiology, Behavioral Phenotyping Core Facility.
authors.forename: Craig
authors.initials: C
authors.lastname: Weiss
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences.
authors.forename: Yong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Interdepartmental Neuroscience Program, Department of Psychiatry and Behavioral Sciences.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Dong
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhai
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences.
authors.forename: Ronggen
authors.initials: R
authors.lastname: Fu
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences.
authors.forename: Erdong
authors.initials: E
authors.lastname: Liu
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences.
authors.forename: Hasan
authors.initials: H
authors.lastname: Arrat
authors.affiliation: Division of Neuropathology, Department of Pathology, Cognitive Neurology and Alzheimer Disease Center, and.
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.affiliation: Department of Physiology.
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
authors.affiliation: Department of Physiology.
authors.forename: Marco
authors.initials: M
authors.lastname: Martina
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mugnaini
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Interdepartmental Neuroscience Program, Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 t-siddique@northwestern.edu h-deng@northwestern.edu.
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, t-siddique@northwestern.edu h-deng@northwestern.edu.
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics / Q000503:physiopathology; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; C405662:UBQLN2 protein, human; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex