Heparan sulfate chain length modulates the cellular targeting of prions in vivo

Abstract

Prion diseases are fatal neurodegenerative disorders caused by the misfolding of the physiologically expressed prion protein into an insoluble form that accumulates as amorphous aggregates (subfibrillar prions) or amyloid fibers (fibrillar prions). Identical prion protein sequences can misfold into different conformational variants or strains that affect specific neural cell populations, leading to a wide variety of clinical signs and brain regions targeted. The mechanisms underlying the cell targeting of prion strains are unknown. Heparan sulfate (HS) molecules are glycosaminoglycans abundantly expressed in the brain and that profoundly vary in length and sulfation depending on the cell type. HS co‐localize with prion plaques of Creutzfeldt–Jakob disease (CJD), Gerstmann‐Sträussler‐Scheinker (GSS) syndrome, and sheep scrapie, and promote prion replication and fibril formation in vitro. Paradoxically, HS have been used to slow or even prevent prion formation in CJD patients and scrapie‐infected rodents. We hypothesize that the interaction of HS with prions is a major determinant underlying the selective cell vulnerability in prion diseases. Here we characterized the HS length that most effectively modulates the in vitro prion conversion into the aggregated state. We also determined how manipulating the HS chain length shifts the cell tropism of prion strains in vivo. While longer HS chain lengths led to more efficient prion conversion for subfibrillar strains (RML and ME7), intermediate lengths were more effective for the fibrillar strain mCWD. Ext1+/‐ mice expressing shorter HS molecules only altered prion disease phenotype when inoculated with the fibrillar prion mCWD, affecting the disease progression and neuropathology. Together these results suggest that the specific length of the HS together with the prion aggregate conformation determine the binding affinity of prions to HS, and underlie the specific cellular targeting in the CNS. These results have implications for other misfolding proteins such as amyloid‐β and α‐synuclein, which also interact with HS.Support or Funding InformationNIH, NINDS R01 grant 069566 Creutzfeldt–Jakob disease Foundation Fundación Ramón ArecesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.