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Sci Transl Med. 2015 Sep 30;7(307):307ra153. doi: 10.1126/scitranslmed.aac8201.

Human endogenous retrovirus-K contributes to motor neuron disease.

Author information

1
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
2
Neurotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
3
Molecular Neurophysiology and Biophysics Section, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
4
Bioinformatics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 21042, USA.
5
Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 21042, USA.
6
Integrated Research Facility, National Institute of Allergy and Infectious Disease, National Institutes of Health, Fort Detrick, Frederick, MD 21042, USA.
7
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.
8
Department of Neurology, Johns Hopkins University, Baltimore, MD 28217, USA.
9
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.

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.

PMID:
26424568
DOI:
10.1126/scitranslmed.aac8201
[Indexed for MEDLINE]

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