Accumulating evidence suggests a link between the activation of endogenous retroviruses (ERVs) and the development of NDs. ERVs are remnants of retroviral germline invasions that have integrated into the host genome throughout evolution.
In this article, we delve into the emerging understanding of how these ERVs, particularly murine leukemia viruses (MLVs), influence ND pathogenesis through their gene products, especially the Env glycoprotein, and their potential involvement in prion-like spreading.
ERVs in Neurodegenerative Diseases
Notably, the expression of HERV-K and HERV-W gene products, such as HERV-W Env46 and HERV-K Env47, has been implicated in neurotoxicity and inflammation, contributing to ND pathogenesis14. The relationship between viral transcripts and inflammatory responses underscores the potential impact of ERV activation on ND development.
Mechanisms of ERV Contribution
A novel mechanism by which ERV gene products may contribute to neurodegeneration has been proposed. It involves the acceleration of intercellular dissemination of protein particles, specifically proteopathic seeds associated with NDs. Polytropic endogenous MLV proviruses, usually epigenetically silenced, were activated in cellular models, leading to the production of infectious virions and the secretion of extracellular vesicles (EVs) loaded with protein aggregates and viral Env. This process substantially increased the intercellular transmission of proteopathic seeds, triggering protein aggregation in recipient cells.
MLV Reactivation and Mechanisms
Reactivation of previously silenced MLV proviruses, likely induced by demethylation of MLV promoter regions, resulted in the emergence of active viruses. These viruses exhibited a polytropic host range due to recombination between derepressed MLV subgroups. Notably, different MLVs can be produced within a single cell population, leading to varied receptor usage for viral particles. The activation of ERVs appeared to be independent of transgene expression or the induction of protein aggregates, and the precise cellular triggers for provirus derepression remain elusive.
Env Glycoprotein and Intercellular Spread
Subsequent cleavage of the MLV Env R-peptide initiated fusion events, releasing proteopathic seeds into recipient cells’ cytosols and inducing aggregate formation. Surprisingly, MLV Env alone was sufficient to enhance intercellular aggregate spreading, similar to other viral glycoproteins’ effects observed in different contexts.
Broad Applicability of the Mechanism
The study’s focus on a model protein for cytosolic aggregates, along with observations of enhanced spreading of Tau aggregates in cells actively producing infectious MLVs, suggests the broader relevance of this mechanism. Prion-like domains found in various proteins associated with NDs, such as FUS and TDP-43, could potentially be affected by ERV derepression. This notion is supported by previous findings of prion-containing EVs and retroviral association with prion-infected cells.
Implications and Future Directions
The link between ERV activation and NDs holds promise for potential therapeutic interventions. Given the correlation between elevated HERV expression and disease progression, targeting ERV gene products’ expression and maturation could serve as a strategy for mitigating NDs. However, further research is needed to unravel the intricate interplay between ERV activation, protein aggregation, and neurodegeneration in different disease contexts.
Conclusion
The emerging understanding of ERVs’ role in NDs sheds light on a novel mechanism for the acceleration of intercellular protein aggregate spreading. The activation of ERVs, particularly MLVs, and the subsequent production of infectious virions and aggregate-loaded EVs highlight the intricate interplay between retroviral elements and ND pathogenesis.
This research opens new avenues for exploring therapeutic interventions that target ERV gene product expression, potentially offering innovative approaches to tackle the progression of neurodegenerative diseases.
In deep…..
Endogenous retroviruses (ERVs) are genetic elements that are derived from ancient retroviruses that have integrated into the human genome. ERVs are present in all human cells and make up about 8% of the human genome. Most ERVs are inactive, but some can become reactivated and cause disease.
There is growing evidence that ERVs may play a role in the development of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In these diseases, ERVs can be reactivated and produce proteins that damage neurons. ERVs can also trigger inflammation and immune responses that can contribute to neurodegeneration.
One way that ERVs can damage neurons is by producing proteins that are toxic to these cells. For example, the HERV-K protein has been shown to be toxic to neurons and to promote the development of Alzheimer’s disease. ERVs can also produce proteins that interfere with the normal function of neurons. For example, the HERV-W protein has been shown to disrupt the production of new neurons.
In addition to producing toxic proteins, ERVs can also trigger inflammation and immune responses that can damage neurons. When ERVs are reactivated, they can produce proteins that are recognized by the immune system as foreign. This can lead to the production of antibodies and other immune cells that can attack neurons. Inflammation and immune responses can also damage neurons by causing them to release harmful molecules.
The role of ERVs in neurodegenerative diseases is complex and not fully understood. However, there is growing evidence that ERVs may play a significant role in the development of these diseases. Further research is needed to better understand the mechanisms by which ERVs contribute to neurodegeneration and to develop new treatments for these diseases.
Here are some specific examples of how ERVs have been implicated in neurodegenerative diseases:
- In Alzheimer’s disease, the HERV-K protein has been shown to be toxic to neurons and to promote the development of the disease.
- In Parkinson’s disease, the HERV-W protein has been shown to disrupt the production of new neurons.
- In ALS, the HERV-E protein has been shown to trigger inflammation and immune responses that can damage neurons.
These are just a few examples of the many ways that ERVs may contribute to neurodegenerative diseases. Further research is needed to better understand the role of ERVs in these diseases and to develop new treatments.
In addition to the research mentioned above, there are several other lines of research that are being pursued to investigate the role of ERVs in neurodegenerative diseases. These include:
- Studying the effects of ERV reactivation on the expression of genes that are involved in neurodegeneration.
- Investigating the role of ERVs in the development of inflammation and immune responses in neurodegenerative diseases.
- Developing new methods to detect and quantify ERVs in the brain.
- Developing new treatments that target ERVs or their products.
The research on the role of ERVs in neurodegenerative diseases is still in its early stages, but it is a promising area of research that could lead to new treatments for these devastating diseases.
reference link: https://www.nature.com/articles/s41467-023-40632-z