2023-09-04 23:40:05
Viral inheritance with consequences: Remnants of viruses in the human genome might accelerate the course of neurodegenerative diseases, as a research group has discovered. Accordingly, these “human endogenous retroviruses” (HERV) contribute to the clumped tau proteins typical of Alzheimer’s spreading in the brain. Viruses encourage this because their proteins facilitate the transport of tau proteins from cell to cell across membrane vesicles.
The genes of endogenous viruses accumulated in the human DNA in the course of evolution and are now naturally contained in the human genome. They make up around ten percent of the human genome. These are remnants of viral genes that lie dormant in the genome as remnants of various viral infections of our distant ancestors. The gene sequences are usually no longer intact or active, but in some cases they can still be read.
In recent years there has also been evidence that endogenous viruses might have an impact on brain development and neurological diseases such as multiple sclerosis.
Targeting endogenous viruses
A possible influence on dementia is now also becoming apparent. So far it has been assumed that viral infections during life can primarily contribute to such neurodegenerative diseases. “However, there is evidence that endogenous retroviruses are activated under certain conditions and contribute to cancer and neurodegenerative diseases,” says senior author Ina Vorberg from the German Center for Neurodegenerative Diseases (DZNE). “In the blood or tissue of patients, one finds proteins or other gene products that come from such retroviruses.”
HERV-W and HERV-K are two such endogenous viruses that occur in the human genome, but are mostly dormant. However, earlier studies indicate that HERV-W is activated in multiple sclerosis and HERV-K in the nerve disease amyotrophic lateral sclerosis (ALS) and in frontotemporal dementia (FTD).
Viral proteins as transport helpers
The researchers led by Vorberg and first author Shu Liu from the DZNE have now examined in more detail what role these endogenous retroviruses play in dementia. They carried out laboratory studies on cell cultures that imitated the situation in the brain as a model: They used, among other things, mouse cells that produced proteins of the endogenous murine leukemia virus, and human cells that produced certain proteins from the envelope of the two endogenous retroviruses HERV-W and HERV-W manufactured HERV-K.
The researchers conducted studies on cell cultures, as seen in this microscopy image. © DZNE / AG Vorberg (S. Heumüller)
In the experiments, the researchers observed that these viral proteins facilitate the transport of certain protein aggregates – clumps of the malformed protein tau – from cell to cell. Tau aggregates occur in the brains of people with neurodegenerative diseases – including Alzheimer’s, ALS and FTD.
The experiments revealed that the endoviral proteins nest in the cell membrane and in the membrane of the transport sacs that are pinched off from the cell, where they serve as transport mediators for the tau aggregates.
With membrane vesicles in other cells
The clumps of protein can thus get from one cell to the next in two ways: either via the membrane fusion of two cells that are in direct contact with each other, or packed inside the vesicles. These small bubbles are pinched off from the cell membrane and can then fuse once more with the membrane of another cell. This transfers the contents of the vesicle.
As Liu and her colleagues found, the endoviral proteins support this process of membrane fusion. “Endogenous retroviruses would not trigger neurodegeneration, but they might fuel the disease process once it has started,” explains Vorberg.
Overall, the researchers come to the conclusion that not only viral infections, but also endogenous retroviruses can be involved in neurodegenerative diseases. They assume that the “sleeping” endogenous retroviruses are “awakened” in the course of the aging process, because the regulation of genes naturally changes with aging and because symptoms of neurodegenerative diseases usually only appear in old age.
New approaches for the therapy of neurodegenerative diseases
The researchers’ findings might one day help people affected by neurodegenerative diseases. On the one hand, one can try to switch off the endogenous viruses that have “awakened” with age so that they do not produce any viral proteins. On the other hand, one might try to neutralize the viral proteins, for example with antibodies from a passive vaccine. However, the necessary drugs do not yet exist; they first have to be developed.
Next, the Bonn research group wants to look for suitable antibodies. The team also wants to test whether existing antiviral drugs can stop the transport of protein aggregates. (Nature Communications, 2023; doi: 10.1038/s41467-023-40632-z)
Source: German Center for Neurodegenerative Diseases eV (DZNE)
5. September 2023
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