Role for endogenous retrovirus proposed in ALS pathogenesis

By Eleanor McDermid, Senior medwireNews Reporter

Expression of the human endogenous retrovirus-K (HERV-K) is upregulated in some patients with sporadic amyotrophic lateral sclerosis (ALS) and causes degeneration of motor neurons when overexpressed in mice, research shows.

“These findings may have implications for a subgroup of ALS patients with increased HERV-K expression”, say Avindra Nath (National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA) and co-researchers.

“Because activation of HERV-K can lead to neurodegeneration, blocking its activation and replication may affect the course of ALS.”

HERV-K is the most recently acquired of a number of retroviruses that have been incorporated into the human genome over time. In line with previous research, Nath et al found that expression of all three of the virus’s major structural genes – gag, pol and env – was significantly upregulated in postmortem brain tissue from 11 sporadic ALS patients compared with that from 10 Alzheimer’s patients and 16 individuals without neurological diseases.

Ten of the 11 ALS patients had strong cortical expression of the env (envelope) protein, and it was also expressed in the anterior horn neurons in the spinal cord, but was not present in the lateral or posterior horns, or in glial cells or white matter.

The team notes that none of the genetic mutations so far associated with ALS explain how the disease spreads through the body. “Our finding that full-length transcripts of HERV-K can be found activated in the brain of some ALS patients raises the possibility that the virus could spread from one neuron to the next and, in the process, lead to neurotoxicity through expression of the env protein.”

As described in Science Translational Medicine, the researchers used cultured human neurons and a transgenic mouse model to demonstrate that the env protein can indeed cause neurodegeneration.

In human neurons, expression of the whole HERV-K genome or of only the env gene caused a reduction in cell numbers and the retraction of neurites. Transgenic mice that expressed env in neurons had reduced numbers of corticospinal motor neurons on immunostaining at the age of 6–9 months and about a 22% reduction in the thickness and volume of the motor cortex on magnetic resonance imaging, with other areas being unaffected. They also had neurodegeneration in the spinal cord, with “near absence of motor neurons at some levels”.

Consistent with this, the mice showed progressive motor dysfunction in behavioural tests. Dysfunction began between 3 and 6 months and 50% of the mice had died by 10 months.

Of note, the team found that HERV-K expression was regulated by trans-activation-responsive DNA-binding protein 43 – the same protein that regulates HIV replication.

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