Endogenous Retrovirus Active in ALS

Researchers uncover evidence that a retrovirus embedded within the human genome may play a role in the pathology of amyotrophic lateral sclerosis

By | September 30, 2015

Transgenic mice expressing the HERV-K env gene suffered neurodegeneration and motor symptoms characteristic of ALS.AVINDRA NATHAn endogenous human retrovirus called HERV-K is expressed at higher levels in the brains of amyotrophic lateral sclerosis (ALS) patients than in those of controls, and the virus is toxic to human neurons in culture, according to a study published this week (September 30) in Science Translational Medicine. Researchers further showed that mice expressing the HERV-K envelope gene develop symptoms of ALS, suggesting that the retrovirus may play a causal role in neurodegeneration.

“The new study is substantial and impressive in that it has employed a wide range of powerful in vivo and in vitro molecular biological, immunological, genetic, and other techniques,” Jeremy Garson, a medical virologist at University College London who was not involved in the work, wrote in an email. “The new data presented in the paper represents a significant contribution to our understanding of the potential role of endogenous retroviruses in neurological disease.”

“It’s a very, very important paper,” said Mount Sinai’s Daniel MacGowan, who also did not participate in the research. But, he added, “it didn’t show the smoking gun [at the molecular level] so there’s still the possibility that it’s an epiphenomenon. . . . We need more brain samples.”

In 2006, neurovirologist Avindra Nath of the National Institute of Neurological Disorders and Stroke saw a young man who had both HIV and ALS. When the patient started taking antiretroviral drugs to treat his HIV, his ALS symptoms improved, Nath recalled. “I thought that was quite fascinating.”

Turning to the literature, Nath discovered that the two diseases did occasionally co-occur. He also found a handful of studies from Garson’s and MacGowan’s groups that reported reverse transcriptase activity—a sign of a retrovirus infection—in the blood of some ALS patients. But when the researchers looked for known exogenous retroviruses such as HIV, they didn’t find any. “I reasoned, if you have reverse transcriptase activity and you can’t find an exogenous retrovirus, maybe there’s an endogenous retrovirus,” Nath said.

Endogenous retroviruses constitute nearly one-tenth of the human genome. While most of these viruses have accumulated mutations that make them inactive, researchers now know that they can sometimes come back to life—and cause major problems. The human T-cell lymphotropic virus type 1, for example, has been implicated in various cancers and may spur neurodegeneration in the spinal cord.

Sure enough, when Nath and his colleagues searched for a variety of human endogenous retroviruses (HERVs), they found elevated levels of HERV-K transcripts in the brain tissue of deceased ALS patients but not in samples from healthy patients or individuals with Parkinson’s disease. In the latest study, Nath’s team explored whether the virus itself is neurotoxic, or if it was simply a byproduct of the motor neuron degeneration characteristic of ALS.

The researchers first synthesized the viral genome and transfected the whole thing or just the envelope gene (env) into cultured human neurons. Both treatments triggered the retraction of cell-body projects called neurites as well as neuronal death. Using CRISPR to activate the endogenous retrovirus in the cultured cells had the same effect. And expressing the HERV-K env gene in mice caused that the animals developed classical symptoms of ALS. Altogether, the results highlight a role for HERV-K in ALS pathology.

“We haven’t proven that the virus causes ALS,” Nath said. “What we’ve shown is that the virus antiviral product may play a role in the pathophysiology of ALS.”

“Although this does not necessarily define primary causality, these data certainly underscore that activation of HERV-K and viral proteins such as env can accelerate motor neuron pathology,” Robert Brown of the University of Massachusetts Medical School and King’s College London’s Ammar Al-Chalabi, who were not involved in the research, agreed in an accompanying commentary. “From a clinical perspective, several important questions arise. . . . Perhaps most importantly, can one now define a cocktail of antiretroviral interventions that are beneficial, and will the activity of the retrovirus prove to be a quantitative biomarker of disease activity?”

Indeed, Nath is eager to see if the identification of HERV-K’s probable role in ALS pathology may provide a new target for drug developers in a field that has for decades come up empty-handed. “Even if you don’t know the cause, if you can find a key molecule in the pathway you can block it and impact the course of the disease,” he said. “We think we have a key molecule.”

W. Li et al., “Human endogenous retrovirus-K contributes to motor neuron disease,” Science Translational Medicine, 7:307ra153, 2015.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 475

October 1, 2015

See also:Riboswitch Flip Kills Bacteria

"... riboswitches—and other RNA elements—might be hitherto unappreciated targets for antibiotics and other drugs."

Has anyone who is not an evolutionary theorist or theoretical physicist under-appreciated epigenetically-effected RNA elements?

RNA-mediated gene duplication and RNA-mediated amino acid substitutions appear to link the stability of organized genomes and the differentiation of all cell types in all individuals of all living genera.

That suggests the instability of Stephen Hawking's genome could be linked to all other virus-driven pathology by a single base pair change and one RNA-mediated amino acid substitution with downstream effects on the microRNA/mesenger RNA balance that would otherwise maintained the organized genome via proper nutrition or supplementation to support the function of the innate immune system that protect us from viruses.

It is shameful that the biologically uninformed have led others who could have become serious scientists to ignore everything known about cell type differentiation by members of the RNA-society and other serious scientists who are biologically informed.

Let's all blame Richard Dawkins for the problems in life that he attributes to religion, shall we? It would not be fair to blame Steve Hawking for his disease and the inability of medical practitioners to find an effective treatment or cure. 

Alternatively, blame no one for their ignorance. But stop them from touting ridiculous theories.

 

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