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Comment
. 2020 Mar 2;130(3):1087-1089.
doi: 10.1172/JCI134842.

Underglycosylated prion protein modulates plaque formation in the brain

Jason C Bartz
Comment

Underglycosylated prion protein modulates plaque formation in the brain

Jason C Bartz. J Clin Invest. .

Abstract

The prion agent is unique in biology and is comprised of prion protein scrapie (PrPSc), a self-templating conformational variant of the host encoded prion protein cellular (PrPC). The deposition patterns of PrPSc in the CNS can vary considerably from a diffuse synaptic pattern to large plaque-like aggregates. Alterations of PrPC posttranslational processing can change PrPSc deposition patterns; however, the mechanism underlying these observations is unclear. In this issue of the JCI, Sevillano and authors determined that parenchymal PrPSc plaques of the mouse brain preferentially incorporated underglycosylated PrPC that had been liberated from the cell surface by the metalloproteinase, ADAM-10, in combination with heparan sulfate. These results provide mechanistic insight into the formation of PrPSc plaques and suggest that PrP posttranslational modifications direct pathogenicity as well as the rate of disease progression.

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Conflict of interest statement

Conflict of interest: The author has declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. Role of posttranslational processing of PrPC in the formation of prion aggregates.
Fibrillar prion strains such as mCWD preferentially incorporate underglycosylated PrPC (blue) that is released from the cell surface by ADAM-10 into plaques that form in association with HS in the parenchyma. Subfibrillar prion stains, such as RML, preferentially incorporate glycosylated PrPC into diffuse synaptic deposits of PrPSc (red) without a HS scaffold. Genetic ablation of N-linked glycosylation sites (N) can switch in nonfibrillar strain pathology from synaptic diffuse deposition to plaque-like deposition of PrPSc in the parenchyma.
See this image and copyright information in PMC

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