title: Human endogenous retrovirus-K contributes to motor neuron disease.
abstract: The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis.
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Wenxue
authors.initials: W
authors.lastname: Li
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Myoung-Hwa
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Henderson
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Tyagi
authors.affiliation: Neurotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Muzna
authors.initials: M
authors.lastname: Bachani
authors.affiliation: Neurotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Steiner
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Campanac
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dax A
authors.initials: DA
authors.lastname: Hoffman
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: von Geldern
authors.affiliation: Bioinformatics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 21042, USA.
authors.forename: Kory
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.affiliation: Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 21042, USA.
authors.forename: H Douglas
authors.initials: HD
authors.lastname: Morris
authors.affiliation: Integrated Research Facility, National Institute of Allergy and Infectious Disease, National Institutes of Health, Fort Detrick, Frederick, MD 21042, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Lentz
authors.affiliation: Laboratory of Muscle Stem Cell and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 21042 , USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Pak
authors.affiliation: Laboratory of Muscle Stem Cell and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 21042 , USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mammen
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 28217, USA.
authors.forename: Lyle
authors.initials: L
authors.lastname: Ostrow
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 28217, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rothstein
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. natha@ninds.nih.gov.
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D000818:Animals; D001522:Behavior, Animal; D001665:Binding Sites; D001921:Brain / Q000473:pathology / Q000821:virology; D004268:DNA-Binding Proteins / Q000378:metabolism; D020077:Endogenous Retroviruses / Q000502:physiology*; D006801:Humans; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D009046:Motor Neurons / Q000473:pathology / Q000821:virology; D009410:Nerve Degeneration / Q000473:pathology; D010641:Phenotype; D020079:Terminal Repeat Sequences / Q000235:genetics; D014775:Virus Activation
chemical_list: D004268:DNA-Binding Proteins