Role for Lipids in the Cellular Transmission of α-Synuclein

The presynaptic protein α-Synuclein (α-Syn) abnormally aggregates in the brains of Parkinson's Disease patients. Evidence suggest a transcellular transfer of an oligomeric form of the protein (seed) in a prion-like fashion. The mechanism underlying cell entry is unclear, but studies have implicated the cell surface glycan HSPG followed by macropinocytosis, as a possible uptake route. Secretion and uptake of aggregated α-Syn was reported to be associated with lipid vesicles in cells. Monomeric α-Syn was found to tubulate membranes in-vitro. This work aims to study the significance of membrane association and tubulation by α-Syn to its effect on uptake by cells. Uptake of lipid-associated α-Syn seeds was significantly more efficient than lipid-free uptake. Furthermore, seeds in the presence of monomers and lipids, which formed tubules in-vitro, were more readily internalized than seeds and lipids in the absence of monomers. Lipid associated α-Syn was internalized by cells in an HSPG dependent manner as evident from competitive inhibition and enzymatic digestion experiments. Tubule associated seeds may constitute an efficient mechanism of pathological propagation of synucleinopathies. This mechanism should be considered in any therapeutic approach targeting the inhibition of α-Syn intercellular transfer.