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Fig. 2 | Translational Neurodegeneration

Fig. 2

From: Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system

Fig. 2

Cell-to-cell spread of prion-like protein species. Prions are proposed to be spread from ‘donor’ to ‘recipient’ cells by numerous mechanisms. ‘Naked’ prions can be released into the extracellular space through either exosomal release or leakage through damaged cell membranes (c and d, respectively), where they can, in turn, become internalised by mechanisms such as direct pinocytosis, a process thought to occur via both clathrin-dependent receptor mediated endocytosis (f) and clathrin-independent endocytosis (g), resulting in intracellular release (j). Heparan sulphate proteoglycans (HSPGs), transmembrane and lipid-anchored cell surface receptors that interact with a variety of ligands, have also been shown to mediate internalisation of prions, via HSPG-mediated micropinocytosis (i): an endocytic process characterized by binding of the prion ligand to surface-bound HSPG, actin-driven membrane ruffling, internalization of extracellular fluids, and formation of large intracellular vacuoles. Prions can also be released within exosomes (a) or ectosomes (b), which can be internalised through vesicular fusion (h). Tunnelling nanotubes, F-actin containing membranous bridges which connect the cytoplasm of remote cells with one another, can also facilitate cell-to-cell exchange (e). Ultimately, once inside the new host cell, prion-like amyloid-prone proteins are thought to initiate amyloid assembly, through recruitment of endogenous natively folded protein monomers or oligomers leading to formation of an initial segment of an amyloid spine (k). This spine can then break, inducing further intracellular propagation of amyloid formation and release of new amyloid ‘seeds’ (l), which can then be released and propagate to new unaffected cells by the aforementioned cell-to-cell translocation pathways

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