Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. The precise mechanism of extracellular aggregate transfer and induction of new aggregates is unclear.
Yet only a small fraction of released soluble or aggregated proteins are associated with extracellular vesicle, while the vast majority is freely secreted.
So there is an apparent paradox: If proteins aggregates are not usually found in extracellular vesicles, how could it be that they are causing aggregates?
The usual explanation is that extracellular vesicles are seeding protein aggregates, which might be a good enough explanation in extracellular medium. Yet in humans only Alzheimer disease has extracellular proteins aggregates but has also intracellular aggregates of Tau protein, for most other diseases, the protein aggregates are only intracellular.
Scientists from the German Center for Neurodegenerative Diseases Bonn (DZNE) and the German Centre for the Protection of Laboratory Animals (Bf3R), hypothesized that for one extracellular vesicle to penetrate in a foreign cell, it has to have ligands are present that bind to receptors on the cell surface and then cause the two membranes to fuse. https://www.nature.com/articles/s41467-021-25855-2
The researchers induced cells to produce viral proteins that mediate target cell binding and membrane fusion. Two proteins were chosen as prime examples: SARS-CoV-2 spike protein S, which stems from the virus causing COVID-19, and vesicular stomatitis virus glycoprotein VSV-G, which occurs in a pathogen that is clinically similar to the Foot-and-mouth disease but from a different family.
Moreover, cells expressing receptors for these viral proteins, and with poor aggregate-inducing activity in recipients were chosen.
They found that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase extracellular aggregates of misfolded proteins in infected cells.
- Expression of viral glycoprotein VSV-G drastically increases cell-to-cell spreading of cytosolic prions
- Enhanced extracellular transmission of Tau aggregation upon VSV-G expression
- VSV-G extracellular vesicle efficiently transmit scrapie prions to recipient cells
There is little about intracellular aggregates in this article, as the researchers' focus is obviously on neurodegenerative animal diseases.
Misfolded proteins are located in the cytosol, proteins fold for a reason, it is the endoplamic reticulum (ER) which folds them. There is no mention of the ER in this article. Yet it looks like that a protein which cause membranes to fuse would destroy organelles like the ER.
The German scientists worked on Tau protein and PrP protein, but there is no mention of TDP-43 and synuclein. Probably because those two proteins are found in (human) intracellular aggregates.
In another recent article, another team found that VSV-G caused marked alterations in cell's secretory trafficking, with VSV-G accumulating mainly in the Golgi complex . https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8059059/ The Golgi apparatus is the dispatch station of protein received from the endoplasmic reticulum (ER). ER is the place where linear proteins just produced by the ribosomes are correctly folded.
So a protein disturbing the ER or Golgi apparatus is certainly creating proteopathies such as the one seen in human neurodegenerescence.
Yet that does not prove that VSV-G is the cause of neurodegenerescence. There is nearly nearly no publications associating VSV-G and neurodegenerescence.
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