Ancient retroviral genes found to contribute to ALS
Amyotrophic lateral sclerosis (ALS) is an incurable disease that kills motor neurons, the brain cells that control the muscles. As a result, symptoms of the disease include difficulty walking, speaking, and breathing, eventually resulting in death. This past week, scientists at the National Institute of Health discovered that the relics of viral genes in the human genome contribute to ALS, and that inhibiting these genes may serve as an effective treatment.
Human endogenous retroviral genes, or HERVs, are dormant genes of ancient viruses that have remained in the human genome for generations. According to Avindra Nath, the director of the National Institute of Neurological Disorders and Stroke at the NIH, while we know very little about these genes, they become active and functionally significant in cases of ALS.
The scientists behind the discovery were first clued in by the presence of reverse transcriptase in the blood of ALS patients. Reverse transcriptase is a protein made from the RNA of retroviruses, like HIV, in order to form DNA strands complimentary to their RNA. Retroviruses can effectively use these DNA strands to infiltrate the host genome.
Of course, many of the patients were not HIV positive, so the presence of reverse transcriptase was attributed to HERVs. This finding was supported by brain samples from the patients, which contained heightened levels of mRNA – the single nucleotide strands that code for proteins – from HERVs as well a protein, env, from a HERV called HERV-K.
To show that the products of HERV-K were harmful to ALS patients, Nath and her team mutated mice to express HERV-K and produce env (2). They found that the mice died prematurely after developing problems walking and breathing. Through autopsy of the mice, they determined that this was caused solely by damage to the motor neurons affected by ALS. A similar enhancement of a gene related to ALS, TDP-43, showed that it also enhanced HERV-K activity.
In short, ALS triggers activity in the HERV-K gene, which activates the release of proteins that degrade motor neurons. By regulating the HERV-K gene, we could see significant decreases in the decline of health experienced by ALS patients. Nath and her team believe that this could be the basis for ALS medications in the future.
References:
1) ScienceDaily. (2015, September 24). Dormant viral genes may awaken to cause ALS.ScienceDaily. Retrieved October 4, 2015 from http://www.sciencedaily.com/releases/2015/10/151001094725.htm
2) W. Li, M.-H. Lee, L. Henderson, R. Tyagi, M. Bachani, J. Steiner, E. Campanac, D. A. Hoffman, G. von Geldern, K. Johnson, D. Maric, H. D. Morris, M. Lentz, K. Pak, A. Mammen, L. Ostrow, J. Rothstein, A. Nath. Human endogenous retrovirus-K contributes to motor neuron disease. Science Translational Medicine, 2015; 7 (307): 307ra153 DOI: 10.1126/scitranslmed.aac8201