Sleeping viruses that lurk inside the human genome may “reawaken” and contribute to the development of motor neuron disease, according to new research published today in the journal Science Translational Medicine.



Human endogenous retroviruses (HERVs) are ancient microbial remnants that integrated into our chromosomes during repeated infections that occurred over several million years of our evolution. Although accounting for up to 8% of human DNA, most of them have acquired multiple genetic mutations that made them harmless, and are usually considered as “junk” DNA.

In 2011, Avindra Nath and his colleagues reported that proteins synthesized by one such virus, called HERV-K, are highly concentrated in the brains of patients who died of amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease which destroys the motor neurons that control speech, movement, swallowing and breathing, leading to death between three to five years after the symptoms first appear.

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In their new study, Nath’s group set out to explore whether the viral proteins are toxic to nerve cells. They examined samples of nervous tissue from 11 patients who had died of ALS, 10 Alzheimer’s patients, and 16 people with no signs of neurological disease, who were used as controls. Using RNA sequencing, they first confirmed that transcripts of three HERV-K genes – the copies of viral DNA used for protein synthesis – are present in the tissue samples from the ALS patients but not those from the Alzheimer’s patients or controls.

They then showed that the proteins encoded by the viral genes are localised to motor neurons in the brains of the ALS patients, and in the front half of the spinal cord, which contains the cell bodies of motor neurons that send their axonal fibres out to the body muscles.

Next, they inserted either the entire viral genome, or just the env gene, which encodes the virus’s coat protein, into human neurons growing in Petri dishes. Once integrated into the cellular DNA, the viral genes are switched on, and use the cell’s molecular machinery to synthesize their respective proteins. Introduction of the viral genome killed significant numbers of cells and caused them to retract their fibres - and the env gene alone was sufficient to do the same.

Expression of HERV-K genes alters the morphology of large pyramidal neurons in the mouse motor cortex (left). Photograph: Nath Lab/ NINDS/ NIH

Finally, the researchers created a strain of genetically engineered mice whose neurons express high levels of the env gene. Behavioural tests revealed that these animals developed impairments in motor function. They had difficulty walking and balancing compared to healthy mice, and these symptoms progressed rapidly between 3 and 6 months of age, killing half of the animals by 10 months of age.

Closer examination revealed that neurons in the motor cortex displayed various structural changes associated with degeneration, such as a decrease in the length, branching and complexity of dendrites, and a reduction in the number of dendritic spines, the tiny, finger-like protuberances which receive chemical signals from other cells.

All of this strongly suggests that reactivation of dormant HERV-K contributes to neurodegeneration in the brain and spinal cord. The absence of the virus in the brains of Alzheimer’s patients supports the conclusion that reactivation causes degeneration, rather than being a consequence of it, and further suggests that it is specific to ALS.

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ALS is associated with genetic mutations in more than 50 different genes, but, as is the case for Alzheimer’s, all of these cause inherited forms of the disease, which account for just 10-15% of cases. But this study only examined patients with sporadic, or non-inherited, ALS, the causes of which have been much harder to pin down.

Further genetic analyses may identify DNA sequence variations, in the HERV-K genes themselves, and others that interact with them, which might make the virus more prone to reactivation. And more work will need to be done to determine exactly how the reactivated virus genes contribute to the disease.

Meanwhile, Nath and his colleagues are collaborating with researchers at Johns Hopkins University to see if anti-retroviral drugs might alleviate disease symptoms in subsets of ALS patients.

Reference: Li, W., et al. (2015). Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Trans. Med., 7: 307ra153. [Abstract]