Activation of Dormant Viruses May Cause ALS


Inactive viruses that litter the human genome may become reactivated 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 the flotsam and jetsam of ancient viruses that integrated into our chromosomes long ago as the results of retrovirus infections that occurred over several million years of our history.  These HERV sequences account for about 8% of human DNA and the vast majority of them have acquired multiple genetic mutations that made rendered them innocuous.  Therefore, HERVs are sometimes referred to as “junk” DNA, although some of these sequences have been shown to have function (for example, see Dupressoir A, Lavialle C, Heidmann T. Placenta. 2012 Sep;33(9):663-7).

In 2011, Avindra Nath, the intramural clinical director of the National Institute of Neurological Disorders and Stroke, and his colleagues reported that proteins synthesized by one such HERV known as HERV-K are found in very high concentrations in the brains of patients who died of amyotrophic lateral sclerosis (ALS), which is a progressive and fatal neurodegenerative disease that destroys those motor neurons that control speech, movement, swallowing and breathing, which leads to death between three to five years after the symptoms first appear.

In their new study, Nath’s research group investigated the toxicity of viral proteins to nerve cells. They examined samples of nervous tissue from 11 patients who had died of ALS, 10 Alzheimer’s patients, and 16 people who showed no signs of neurological disease as controls.  They used RNA sequencing to confirm that transcripts of three HERV-K genes are present in tissue samples from the ALS patients but not in those from the Alzheimer’s patients or control patients.  In their next set of experiments, Nath and his coworkers showed that the proteins encoded by these viral genes localized to motor neurons in the brains and front halves of the spinal cords of ALS patients.  This is significant, since the ventral or font portions of the spinal cord contains the cell bodies of motor neurons that send their axonal fibers to the body’s skeletal muscles where they synapse with those muscles.  Thus the presence of the viral proteins strongly correlates with the tendency of these cells to die.

To definitively test the toxicity of these viral proteins to neurons, Nath and others transfected either the entire viral genome, or just the viral env gene, which encodes the virus’s coat protein, into cultured human neurons.  Once integrated into the genomes of the cultured cells, the viral genes were fully activated and used the cell’s molecular machinery to synthesize their respective proteins.  Expression of these viral genes killed off significant numbers of cells and caused them to retract their neural fibers.  Furthermore expression of only the env gene in these cultured neurons was sufficient to kill them.

To test their hypothesis in a living animal, Nath and others generated a strain of genetically engineered mice whose neurons express high levels of the HERV-K env gene.  Behavioral tests showed that these HERV-K env+ animals developed motor function abnormalities; they had difficulty walking and balancing compared to healthy mice.  These symptoms progressed rapidly between 3 and 6 months of age, and half of the animals had died before or shortly after reaching 10 months of age.

Closer examination revealed that neurons in the motor cortex had degenerated.  They also showed a decrease in the length, branching and complexity of dendrites, and a reduction in the number of dendritic spines (small, finger-like extensions that receive chemical signals from other cells).

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

ALS is associated with genetic mutations in more than 50 different genes.  However, as is the case for Alzheimer’s, these 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 cause 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.  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 determine if anti-retroviral drugs might alleviate disease symptoms in subsets of ALS patients.

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

Advertisements

Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).