Scientists at the National Institutes of Health discovered that reactivation of ancient viral genes embedded in the human genome may cause the destruction of neurons in some forms of Amyotrophic Lateral Sclerosis (ALS), also known as Motor Neurone Disease (MND). The results suggest a link between human endogenous retroviral genes (HERVs) and ALS/MND. The findings also raise the question of whether antiretroviral drugs, similar to those used for suppressing HIV, may help some ALS/MND patients.
In a paper published Sept 30th in Science Translational Medicine. Li, et al described elevations of transcripts (RNA’s) for the human endogenous retrovirus HERV-K in ALS brain and spinal cord postmortem tissues. Li, et al generated a transgenic mouse line expressing the envelope (env) gene of HERV-K in neurons and produced mice that underwent degeneration of motor neurons in cortex and spinal cord. The degeneration of neurons in these mice was restricted to upper and lower motor neurons, in spite of widespread expression of env in many different neuron types. The mice developed many motor deficits, reminiscent of genetic ALS/MND mice.
Li, et al showed that the nuclear protein TDP-43, which can activate many viruses including HERV-K, bound to the “long terminal repeat” region of the retrovirus. TDP-43, which is elevated and translocated to cytoplasm in many ALS/MND cases, may regulate HERV-K expression. DNA breakage was found in the affected neurons, suggesting this as a possible toxicity mechanism of HERV-K in the mice.
What might the findings of Li, et al mean for ALS/MND pathogenesis and treatment? Retroviruses are RNA viruses that may represent the earliest life forms on earth. Retroviruses infect cells and change their RNA to DNA, using “reverse transcriptase” enzyme, which they also encode with their pol genes. Once their RNA is changed to DNA, they incorporate some or all of their DNA into the host cell genome and can be passed from generation to generation. Li, et al begin their paper by pointing out that 8% of the human genome contains retrovirus sequences. This DNA used to be called “junk DNA”, but we now realize that it can have many other positive and negative roles in cell function
HIV is a retrovirus, and the first effective anti-HIV drugs were “reverse transcriptase inhibitors” (RTI). The question then arises as to whether RTI’s would be a good therapy for ALS/MND. Caution is needed, because there is much we do not know about whether HERV’s are causal for ALS/MND neurodegeneration. Their presence in ALS/MND tissues may represent an interesting epiphenomenon, or indeed they might be causal for degeneration of motor neurons in a subgroup.
It would be very premature for any ALS/MND patient to start taking any RTI drugs until much more is known, especially since RTI drugs inhibit mitochondrial DNA replication, and impaired mitochondrial function can be found in multiple ALS/MND tissues including spinal cord. Responsible medical practitioners will not prescribe, recommend or help obtain anti-viral drugs for those with ALS/MND at this time or in the near future based on this preliminary research. Please do not risk further neurological or systemic harm by attempting to secure such medications.
W. Li et al., “Human endogenous retrovirus-K contributes to motor neuron disease,” Science Translational Medicine, 7:307ra153, 2015.