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Liu S, Hossinger A, Heumüller SE, Hornberger A, Buravlova O, Konstantoulea K, Müller SA, Paulsen L, Rousseau F, Schymkowitz J, Lichtenthaler SF, Neumann M, Denner P, Vorberg IM. Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions. Nat Commun. 2021 Oct 19;12(1):5739. PubMed.
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Emory University
A link between infectious pathogens and neurodegenerative disorders later in life is plausible but mechanistically enigmatic. It is fair to say that no single infectious agent is the cause of Alzheimer's disease (Walker, 2020), as has been proposed by advocates of diverse microbes and viruses (see, e.g., Itzhaki et al., 2020; Itzhaki et al., 2016; Sochocka et al., 2017). However, there is good evidence that certain infections are risk factors for the disease (Walker, 2020).
In this compelling investigation in cultured cells, Liu and colleagues present evidence that two viral glycoproteins—VSV-G and CoV-2 spike S—each promote the spread of prions and tau proteopathic seeds among cells. The findings indicate that specific receptor-ligand interactions expedite the fusion of extracellular, seed-laden donor vesicles with recipient cells. Interestingly, while glycoproteins from different types of viruses can facilitate the spread of proteopathic seeds, they do so with different efficiencies.
These results suggest a conceivable means whereby infections of various types might augment the probability of developing a neurodegenerative disease later in life. They also might help explain why some infectious agents are stronger risk factors for Alzheimer's disease than are others. The analysis includes a nice experimental progression from yeast prions to pathogenic agents in humans, though it will be important to extend the cell culture findings to animal models. One question, for example, is whether the age at which an infection occurs influences the risk of later neurodegenerative disease—is infection at older or younger ages more problematic? Is there a cumulative effect of multiple infections? Might different pathogens interact to further increase disease risk?
It also will be interesting to determine whether this process of intercellular spread applies to other neurodegenerative proteopathies, such as the synucleinopathies. From a translational standpoint, the study suggests that blocking the receptor-ligand interactions that enable the transfer of cargo from one cell to another might reduce both the pathogenicity of an infectious agent and its downstream impact on the risk of neurodegenerative disease.
References:
Itzhaki RF, Golde TE, Heneka MT, Readhead B. Do infections have a role in the pathogenesis of Alzheimer disease?. Nat Rev Neurol. 2020 Apr;16(4):193-197. Epub 2020 Mar 9 PubMed.
Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, Letenneur L, Lövheim H, Mancuso R, Miklossy J, Otth C, Palamara AT, Perry G, Preston C, Pretorius E, Strandberg T, Tabet N, Taylor-Robinson SD, Whittum-Hudson JA. Microbes and Alzheimer's Disease. J Alzheimers Dis. 2016;51(4):979-84. PubMed.
Sochocka M, Zwolińska K, Leszek J. The infectious etiology of Alzheimer's Disease. Curr Neuropharmacol. 2017 Mar 13; PubMed.
Walker LC. Aβ Plaques. Free Neuropathol. 2020;1 Epub 2020 Oct 30 PubMed.
View all comments by Lary WalkerMayo Clinic Florida
This is an interesting study showing the potential of virus-infected cells for spreading of extracellular vesicles (EVs) containing protein aggregates. It earmarks viral glycoprotein for enhanced binding and endocytosis of EVs to recipient cells for subsequent spread of protein aggregates.
The study tested VSV-G and SARS-CoV-2 spike S viral proteins and the prion domain NM of Saccharomyces cerevisiae Sup35 fused with GFP, the mutated 4R domain of Tau fused with GFP, and the scrapie strain 22 L (N2a22L) as transiently expressed prion seeds. Although the study is limited to overexpression systems using immortalized cell lines, the results are striking and may have translational relevance for virus infection-mediated enhancement of tau propagation via EVs, including via COVID-19, HSV, or HIV infection. The study would be more convincing if the key findings were reproduced in more physiological conditions, such as primary cultured neurons or animal models using physiological protein aggregates as seeds.
We have originally reported the role of EVs for tau propagation (Asai et al., 2015), which was further enhanced in the presence of amyloid plaque in the brain (Clayton et al., 2021). We have also recently shown that AD-brain-derived EV-mediated tau propagation is more efficient than the same amount of tau in fibril or oligomer forms (Ruan et al., 2021).
This study could be evaluated using the tau-propagation mouse model or human brain-derived EV from virus-infected cases in a similar manner. The study also shows that VSV-G loaded EVs endocytose into recipient cells via clathrin-dependent endocytosis, presumably via receptor-mediated endocytosis. This is different from conventional EV uptake, which is by macropinocytosis, and the endocytosis may lead to endolysosomal degradation of the EVs. Indeed, suppression of this pathway is known to enhance tau propagation in recipient cells, which is different from this report. It is unclear how protein seeds can escape this degradation pathway and be efficiently propagated in recipient cells.
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