Figure 2.

Potential mechanisms for exit of native and misfolded proteins from a donor cell and entry of exogenous seeds into a recipient cell. Proteins from a donor cell (blue) can exit by one of at least three pathways: (a) direct secretion of the free protein into the extracellular space by a currently unknown mechanism, (b) secretion in exosomes, or (c) direct transfer through tunneling nanotubes (TNTs). While these mechanisms have been reported to occur under physiological conditions, the role of secretion/release of normally intracellular proteins in brain function is unclear. Once in the extracellular space, free exogenous seeds (red) may then be taken up by a recipient cell by (d) direct insertion through the plasma membrane, (e) fluid-phase endocytosis or macropinocytosis, or (f) receptor-mediated endocytosis. If taken up through an endosome (g), exogenous seeds can escape the vesicle into the cytosol through a mechanism that is unclear. Seeds delivered to a recipient cell by exosomes or TNTs are directly released into the intracellular space. Once exogenous seeds are in the cytosol of the recipient cell (h), they may begin recruiting native monomer (green) and initiate templated misfolding, leading to the formation of oligomers/fibrils and eventually aggregates in the recipient cell.