Figure 2. Models of cell-to-cell protein transmission.

This diagram illustrates potential mechanisms by which misfolded/aggregated proteins are transmitted from one neuron to another. Proteins may be released from neurons via vesicle-mediated exocytosis (1) or simple leakage through damaged membranes (2), then internalize into neighboring neurons either via endocytosis or via direct penetration of the memebrane. Alternatively, as reported with the prion protein, proteins may be transmitted to the neighboring neurons by packaging into exosomes (3) or through tunneling nanotubes (4). Some or all of these mechanisms might work simultaneously, with a specific protein preferring a certain pathway to others. These mechanisms might act between the cell bodies, but could also occur trans-synaptically (5). Internalized aggregates (orange) might act as seeds for the aggregation of the endogenous native proteins (green). This seeded aggregation may produce toxic aggregate species during the course of dynamic aggregation process, which ultimately leads to the formation of pathological inclusion bodies.