Humans may produce upwards of 100,000 proteins. Each different type of protein normally folds into a unique shape (its tertiary structure) that is essential to its function. Proteins can misfold due to mutations that change the amino acid sequence of the protein leading to a defective protein. Alternatively, sometimes a wild-type protein (the normal protein) just undergoes a spontaneous event where the protein loses its natural shape and adopts an abnormal conformation. In most cases, these misfolded proteins are degraded and removed from the cells. However, a common theme with several neurodegenerative diseases is the accumulation of misfolded, degradation-resistant proteins. For Alzheimer’s disease it’s the amyloid-beta and tau proteins, for Parkinson’s disease it’s a protein called alpha-synuclein, and for prion diseases, it’s the PrP protein (see my previous blog Dangerous Vocations). Collectively, these disease-causing abnormal proteins are called proteopathic seeds. In these special disease cases, the initial misfolded protein can induce further misfolding of its normal counterpart proteins. One misfolded protein can bind to a normal protein and cause the normal protein to convert to the aberrant configuration so that now there are two misfolded proteins. Each of these two can bind another normal protein and convert them so that now there are four abnormal proteins. This process continues slowly but steadily and over time the misfolded proteins accumulate within the cell leading to cellular dysfunction. Additionally, the abnormal proteins can spread to other cells so that the pathology expands within the brain until the damage is great enough to manifest in clinical symptoms.
There are likely multiple processes by which this cell-to-cell transmission of misfolded proteins occurs, one of which is via extracellular vesicles (EVs). EVs are small, membrane-bound spheres that bud from the surface of cells and carry within them material from the cytoplasm of the producing cell. Released EVs also have molecules on their surface, called ligands. When an EV encounters a cell that has a receptor for the ligand then the EV will bind to that cell and release its contents into the recipient cell. If the cell producing the EV harbored misfolded proteins which were internalized by the EV then the misfolded proteins would be delivered to the recipient cell. In this way, the disease can spread from cell to cell leading to pathology in each new cell that receives the deadly cargo.
To add more complexity to the neurodegenerative disease puzzle, there have been long-standing suggestions that certain viral infections may also play a role in these illnesses, at least in some individuals. A favored hypothesis is that viruses can induce an inflammatory immune response in the brain that somehow initiates or stimulates the aberrant folding process. Some implicated viruses, such as herpes simplex, can directly infect the brain and cause inflammation. Other implicated viruses, influenza for example, don’t infect the brain but can cause severe systemic inflammation that affects the brain. This inflammation model could explain why widely different viruses have been associated with the development of neurodegenerative illnesses, but this may not be the only way in which viruses act. A newly published study in Nature Communications proposes a novel mechanism whereby viral proteins incorporated into EV membranes can serve as ligands to enhance the binding of EVs to target cells. Like EVs, all viruses have viral proteins on their surface that function as ligands. If a cell has a receptor that can bind the viral ligand then the virus will attach to that cell and initiate the infectious process. The interactions of viral ligands with their corresponding cellular receptors are usually quite effective since this is the mechanism viruses use to spread from cell to cell. Additionally, the host molecules that some viruses use as receptors are common to many cell types so that the virus can infect a broad array of different cells, unlike EVs that are generally more limited in their target cells. Previous work showed that EVs formed from virus-infected cells contain viral proteins on the EV surface, and this study examined whether or not these viral proteins might act as new and highly efficient ligands for the EVs. To test this concept, the study authors examined two viral surface proteins, the G protein from vesicular stomatitis virus and the spike protein from SARS-CoV-2. Using cell culture model systems they showed that the addition of either viral protein to the EVs enhanced the transmission of proteopathic seed proteins to recipient cells expressing the appropriate viral receptor. This suggests that natural viral infection of a cell containing proteopathic seed proteins could produce hybrid EVs decorated with viral ligands and carrying the disease-causing proteins. The authors postulate that such hybrid EVs should spread the abnormal proteins more effectively and to a wider variety of cells than standard EVs. This enhanced transmission of a proteopathic seed protein could be the trigger to initiate disease or stimulate its progression. These results add an intriguing new concept for how widely disparate viral infections might trigger neurodegenerative disease in some individuals. However, it is important to keep in mind that these in vitro cell culture results haven’t yet been confirmed in animal models or human studies, so this hypothesis is still very speculative and much work remains.