Fibrillar structure and charge determine the interaction of polyglutamine protein aggregates with the cell surface.


The pathogenesis of most neurodegenerative diseases – including transmissible diseases like prion encephalopathy, inherited disorders like Huntington disease, and sporadic diseases like Alzheimer and Parkinson diseases – is intimately linked to the formation of fibrillar protein aggregates. It is becoming increasingly appreciated that prion-like intercellular transmission of protein aggregates can contribute to the stereotypical spread of disease pathology within the brain, but the mechanisms underlying the binding and uptake of protein aggregates by mammalian cells are largely uninvestigated. We have investigated the properties of polyglutamine (polyQ) aggregates that endow them with the ability to bind to mammalian cells in culture and the properties of the cell surface that facilitate such uptake. Binding and internalization of polyQ aggregates is a common feature of mammalian cells, and depends upon both trypsin-sensitive and trypsin-resistant saturable sites on the cell surface, suggesting the involvement of cell surface proteins in this process. PolyQ aggregate binding depends upon the presence of a fibrillar, amyloid-like structure and does not depend upon electrostatic interaction of fibrils with the cell surface. Sequences in the huntingtin protein which flank the amyloid-forming polyQ tract also influence the extent to which aggregates are able to bind to cell surfaces.


Source: The Journal of Biological Chemistry


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