title: Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice.
abstract: Mutations in valosin-containing protein (VCP) cause a rare, autosomal dominant disease called inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). One-third of patients with IBMPFD develop frontotemporal dementia, characterized by an extensive neurodegeneration in the frontal and temporal lobes. Neuropathologic hallmarks include nuclear and cytosolic inclusions positive to ubiquitin and transactive response DNA-binding protein 43 (TDP-43) in neurons and glial activation in affected regions. However, the pathogenic mechanisms by which mutant VCP triggers neurodegeneration remain unknown. Herein, we generated a mouse model selectively overexpressing a human mutant VCP in neurons to study pathogenic mechanisms of mutant VCP-mediated neurodegeneration and cognitive impairment. The overexpression of VCPA232E mutation in forebrain regions produced significant progressive impairments of cognitive function, including deficits in spatial memory, object recognition, and fear conditioning. Although overexpressed or endogenous VCP did not seem to focally aggregate inside neurons, TDP-43 and ubiquitin accumulated with age in transgenic mouse brains. TDP-43 was also found to co-localize with stress granules in the cytosolic compartment. Together with the appearance of high-molecular-weight TDP-43 in cytosolic fractions, these findings demonstrate the mislocalization and accumulation of abnormal TDP-43 in the cytosol of transgenic mice, which likely lead to an increase in cellular stress and cognitive impairment. Taken together, these results highlight an important pathologic link between VCP and cognition.
authors.affiliation: School of Natural Sciences, University of California, Merced, California 95343, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Rodriguez-Ortiz
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hoshino
authors.forename: David
authors.initials: D
authors.lastname: Cheng
authors.forename: Liqun
authors.initials: L
authors.lastname: Liu-Yescevitz
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004924:Escape Reaction; D005239:Fear; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000523:psychology; D006185:Habituation, Psychophysiologic; D006801:Humans; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000523:psychology; D009154:Mutation / Q000235:genetics*; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000523:psychology; D009474:Neurons / Q000378:metabolism; D010001:Osteitis Deformans / Q000235:genetics* / Q000523:psychology; D016548:Prosencephalon / Q000378:metabolism; D021641:Recognition, Psychology; D025801:Ubiquitin / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025801:Ubiquitin; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse