Neurodegenerative diseases, a group of debilitating conditions affecting millions worldwide, have long been associated with viral infections. However, a recent breakthrough study by researchers at the German Center for Neurodegenerative Diseases (DZNE) has unveiled a novel mechanism implicating “endogenous retroviruses” present in the human genome. These genetic remnants of ancient viruses, which were thought to be dormant, could play a pivotal role in the development and progression of neurodegenerative disorders. The findings, published in the esteemed journal Nature Communications, highlight the potential therapeutic significance of these “viral relicts” as targets for innovative treatments.
The hypothesis of viral infections contributing to the inception of neurodegenerative diseases has been under investigation for some time. DZNE scientists have now introduced an intriguing angle, uncovering a mechanism that operates without the need for external viral pathogens. Instead, they have turned their focus to “endogenous retroviruses” which have long resided within the human genome. Over time, various genes originating from different viruses have accumulated in human DNA, with most of these gene sequences remaining silent due to mutations. However, evidence has emerged suggesting that under specific conditions, these endogenous retroviruses can be activated and could potentially contribute to the development of conditions such as cancer and neurodegenerative diseases.
Dr. Ina Vorberg, a research group leader at DZNE and a professor at the University of Bonn, explained
During evolution, genes from numerous viruses have accumulated in our DNA. Most of these gene sequences are mutated and normally muted. However, there is evidence that endogenous retroviruses are activated under certain conditions and contribute to cancer and neurodegenerative diseases. Indeed, proteins or other gene products derived from such retroviruses are found in the blood or tissue of patients.
The research journey embarked upon by Dr. Vorberg and her colleagues led them to experiment with cell cultures. They aimed to mimic the conditions under which human cells produce specific proteins from the envelope of endogenous retroviruses. Particularly, their investigation involved two specific retroviruses, HERV-W and HERV K, which are typically dormant in the human genome. Intriguingly, studies have indicated that HERV-W becomes active in multiple sclerosis, while HERV-K activation is associated with the neurological disorders ALS and frontotemporal dementia (FTD). The researchers discovered that viral proteins facilitate the transport of “tau aggregates,” small protein clusters that accumulate in the brains of individuals affected by neurodegenerative diseases like Alzheimer’s and FTD. This breakthrough reveals a potential link between endogenous retroviruses and the spread of tau aggregates between cells in the brain.
The study underscores that while endogenous retroviruses may not initiate neurodegeneration, they could significantly contribute to the disease’s progression once it has begun. The researchers suggest that viral proteins serve as mediators for the transport of tau aggregates. These proteins embed themselves into cell membranes and the membranes of extracellular vesicles, tiny lipid bubbles naturally secreted by cells. This process appears to promote the easier spread of tau aggregates between cells.
As we age, gene regulation can change, potentially reactivating these initially dormant endogenous retroviruses. Notably, most symptoms of neurodegenerative diseases manifest in older age, providing potential targets for therapeutic intervention. Dr. Vorberg outlines two conceivable approaches: “On the one hand, one could try to specifically suppress gene expression, that is, to inactivate the endogenous retroviruses again. That would get to the root of the problem. But you could also start elsewhere and try to neutralize the viral proteins — for example, with antibodies.”
The researchers are hopeful that individuals with dementia and tau aggregates might possess elevated levels of antibodies against these viral proteins. Isolating and replicating these antibodies through biotechnological methods could pave the way for a passive vaccine. Dr. Vorberg’s team, in collaboration with DZNE colleagues, is actively searching for such antibodies in patients, aiming to identify potential therapeutic avenues. Additionally, antiviral drugs have shown promise in cell culture experiments by halting the spread of protein aggregates, suggesting another avenue for exploration.
This groundbreaking research shines a spotlight on the intricate interplay between ancient viral remnants within our genome and the development of neurodegenerative diseases. By unraveling these hidden mechanisms, researchers are inching closer to unveiling innovative treatments that could potentially alleviate the burden of these devastating conditions. As the journey towards a deeper understanding continues, the hope for effective therapies for neurodegenerative diseases grows stronger.