Abstract/Journal Article

DZNE-2020-00565

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png P.16: Glycosaminoglycan modulationaffects cellular prion replicationdownstream of PrPSc internalization

Wolf, H. (First author)DZNE* ; Pleschka, C.DZNE* ; Graßmann, A.DZNE* ; Hossinger, A.DZNE* ; Möhl, C.DZNE* ; Paulsen, L.DZNE* ; Vorberg, I. (Last author)DZNE*

2015

Abstract: Prions are unconventional infectious agentscomposed primarily of misfolded aggregatedhost prion protein PrP, termed PrPSc. Conversion of cellular prion protein into PrPSc occurson the cell surface or along the endocytic pathway. The precise mechanisms and cellularrequirements for PrPSc uptake, the initial PrPScformation and the persistent PrPSc propagationstill remain unknown. Glycosaminoglycans(GAGs), highly-sulfated unbranched polysaccharides present on the cell surface and withinendocytic vesicles, have been implicated as firstattachment sites for prions and cofactors for replication. GAG mimetics and obstruction ofGAG sulfation affect prion replication, but sofar, comparative analysis of the role of GAGsduring the individual stages of infection by 22Lprion strain has not been performed. We examined the effect of the GAG mimetic, DS-500,and the sulfation inhibitor, NaClO3, on prioninfection by scrapie strain 22L in L929 cellsand organotypic cerebellar slices. Here weshow that both compounds change the cellulardistribution and levels of sulfated GAGs buthave divergent effects on cell surface and totalPrPC levels in L929 cells. Chemical manipulation of GAGs did not prevent PrPSc uptake,arguing against their role as essential attachment sites. Importantly, GAG undersulfationand DS-500 effectively antagonized de novoand chronic 22L prion infection in L929 cellsand organotypic cerebellar slices. We concludethat DS-500 and NaClO3 affect events downstream of the initial PrPSc attachment andinternalization.

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Contributing Institute(s):

1. Prion Cell Biology (AG Vorberg)
2. Image and Data Analysis (CRFS-IDAF) (IDAF)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Experiment(s):

1. Image and Data Analysis Facility (CRFS-IDAF) / Bonn

Appears in the scientific report 2015

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Database coverage:
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