Our last posting was a review of sorts of The Theory of Everything, a movie biography of Stephen Hawking and his wife Jane Wilde (1). Hawking was the first to put forward a cosmology based on an attempt to combine general relativity and quantum mechanics. However, in 1963, before Hawking began his groundbreaking studies, he was diagnosed with the neurodegenerative disease, amyotrophic lateral sclerosis (ALS; commonly known as Lou Gehrig’s disease). He was 21 years old and given a life expectancy of only two years. Even after Hawking become a world-renowned scientist, he was totally dependent on Jane at home.
ALS has been a poorly understood and incurable disease, involving the death of neurons that control voluntary movements, speech, and breathing. The illness is usually fatal within three years of the onset of symptom, thus accounting for Hawking’s grim initial prognosis. Now, new evidence, from a research team at the NIH, headed by Avindra Nath, shows that a human endogenous retrovirus, HERV-K, likely plays a key role in the pathology of ALS (2).
Endogenous retroviruses probably arose millions of years ago, when retroviruses first began inserting their provirus (DNA) genomes into the genomes of germ line cells (see reference 3). Astonishingly, eight percent or more of the human genome is comprised of retroelements. Most of these are defective because of the accumulation of numerous mutations over time. Nearly nothing had been known with certainty about their relevance to human disease, although they had been implicated in a variety of illnesses, including cancer, inflammatory disorders, and neurodegeneration.
The new NIH study was prompted by several earlier observations. First, ALS can present as a rare complication in AIDS patients. Second, the ALS symptoms of at least some of these AIDS patients were alleviated by anti-retroviral therapy against their HIV infections. Third, reverse transcriptase activity was detected in the blood of some ALS patients. Fourth, despite an extensive search for exogenous retroviruses in ALS patients, none has ever been detected.
HERV-K, like other retroviruses, has three major structural genes, gag, pol, and env, which encode the viral capsid protein, reverse transcriptase, and envelope proteins, respectively. Nath and co-workers detected transcripts of each of these genes in postmortem brain tissue samples from ALS patients, thus implying that the entire HERV-K genome was expressed in these patient samples. No significant expression of other HERVs was detected in these patient samples. Nor was HERV-K expression detected in brain tissue from healthy individuals, nor was it seen in brain specimens from Alzheimer’s and Parkinson’s disease patients.
ALS patient samples were immunostained for the HERV-K env protein in order to identify the cell types in which the endogenous retrovirus was expressed in those individuals. Env was detected only in large pyramidal neurons in the cortex, and in anterior horn neurons of the spinal cord.
Next, the entire HERV-K genome and env alone were transfected into human neuronal cell cultures to evaluate whether HERV-K expression might be neurotoxic. Env alone, as well as the entire HERV-K genome, caused a decrease in cell numbers and a retraction of axons. Thus, the HERV-K env protein alone causes neurotoxicity and neuronal death in vitro.
The authors then assessed whether the HERV-K env protein might be neurotoxic in vivo; first by in utero electroporation of the env gene into embryonic mouse brain, and then by generating env-expressing transgenic animals. Expression of the HERV-K env in vivo indeed caused degeneration of motor neurons. And, as in ALS patients, only those motor neurons in the transgenic mice that control movements were damaged. Moreover, the transgenic animals developed progressive motor dysfunction, and 50% of the animals died by 10 months of age. The authors note that the mechanism by which the HERV-K env protein leads to neuronal injury is not yet known.
More than 12,000 Americans are currently living with ALS, and there is not yet any effective treatment for them. The current study offers hope that antiretroviral therapy, similar to that used to treat AIDS patients, might benefit at least some individuals suffering from this tragic illness. Be on the lookout for follow-up studies to this report, which are sure to occur.
“Today I consider myself the luckiest man on the face of the Earth…”
References:
1. “The Theory of Everything,” Posted on the blog September 15, 2015
2. Wenxue Li, Myoung-Hwa Lee, Lisa Henderson, Richa Tyag, Muzna Bachani, Joseph Steiner, Emilie Campanac, Dax A. Hoffman, Gloria von Geldern, Kory Johnson, Dragan Maric, H. Douglas Morris, Margaret Lentz, Katherine Pak, Andrew Mammen, Lyle Ostrow, Jeffrey Rothstein and Avindra Nath. Human endogenous retrovirus-K contributes to motor neuron disease, Science Translational Medicine, 7:307ra153 (2015).
3. Howard Temin: In From the Cold, Posted on the blog December 14, 2013.
Leonard Norkin Virology Site 