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Liu S, Heumueller SE, Hossinger A, Mueller SA, Buravlova O, Lichtenthaler SF, Denner P, Vorberg IM. Endogenous retroviruses promote prion-like spreading of proteopathic seeds. 2022 May 06 10.1101/2022.05.06.490866 (version 1) bioRxiv.
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Mayo Clinic Florida
This is an extension of this group's previous paper published in 2021 and is further supporting the in vitro evidence that retrovirus activation potentially enhances intracellular aggregation of proteins. XP1 as the viral receptor for the potential target of intervention and the use of amprenavir to suppress retrovirus protein maturation is intriguing.
The characterization of the involvement of EVs in the transmission process is not rigorously tested, as most of the experiments are not conducted with isolated EVs. This applies to their examination for tau aggregation, which is conducted by co-cultures of donor and recipient cells. The lack of validation in primary cultured cells also remains as a concern.
View all comments by Tsuneya IkezuBoston University School of Medicine
This work presents a new twist on factors that might promote seeding and propagation of protein aggregates. The authors find that production of endogenous retroviruses can promote formation of extracellular vesicles (EVs) that contain and propagate protein aggregates such as the Sup35 prion protein or tau aggregates. The mechanism is plausible because groups such as Josh Dubnau’s, Bess Frost’s, and Josh Shulman’s have shown increased production of viral genes in models of neurodegenerative disease.
The Vorberg group shows that induction of aggregation can reactivate latent endogenous retroviruses, which then stimulate the generation of EVs containing aggregates. Importantly, the group shows that inhibiting viral production of EV production inhibits propagation/seeding.
Although interesting, the work also has important limitations. It is entirely done with dividing cells, such as murine N2a neuroblastoma or human HEK cells. These are cell lines, which are by definition dividing cells and have very different biologies than nondividing neurons or other cell types, such as astrocytes or microglia.
In addition, even if proven, a classic quantitative question remains: While this can be shown in an experimental cell line, to what extent does the process accelerate the disease process in humans? This last question is a huge challenge for all of us working in preclinical models in that our systems might overestimate actual effects in patients. Nevertheless, this work adds to our knowledge of the pathophysiology of disease and could prove to be very important in particular subsets of patients.
View all comments by Benjamin WolozinEmory University
This intriguing research from the Vorberg lab makes a strong case for the potential involvement of endogenous retroviruses (ERVs) in the spread of proteopathic seeds. The integration of work on yeast prions with mammalian cell culture models is a nice example of how basic biological investigations can illuminate disease mechanisms. ERVs are a salient component of the human genome, and they have been implicated in other aspects of neurodegenerative pathobiology such as neurotoxicity and inflammation. This study further indicates that de-repression of ERVs increases the intercellular transfer of pathogenic proteins such as aberrant tau.
The experiments suggest that the spread of other proteopathic seeds might be similarly amplified by ERVs; in this regard, it would be interesting to know if the spread of Aβ—the probable prime mover of Alzheimer's disease—also is promoted by ERVs. As a next step, it will be important to extend the insights gained from in vitro work to animal models.
For instance, advancing age is the most prevalent risk factor for most neurodegenerative diseases; if aging increases the risk of neurodegenerative disease via the de-repression of ERVs, how and when does it do so? And how might this be mitigated pharmacologically? If the strategy can be validated in vivo, these elegant cell culture experiments suggest a new approach to delaying or preventing neurodegenerative diseases.
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