Abstract/Journal Article

DZNE-2020-00717

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png P.61: Prion infection impairs lysosomal maturation—a possible mechanism to sustain prionpropagation

Vorberg, I.DZNE*

2014

Abstract: PrPC as well as PrPSc are glycosyl-phosphatidyl-inositol (GPI)anchored proteins that localize to lipid rafts, which are detergent resistant membrane microdomains characterized by a highcholesterol and sphingolipid content. Cellular cholesterol whichis essential for the formation of lipid rafts can be acquired by endogenous synthesis and uptake from external sources, and theseprocesses are tightly regulated by a feedback loop. Inhibition ofcellular cholesterol synthesis or its extraction and complexation atthe plasma membrane, respectively, interferes with PrPSc propagation in prion-infected cultured cells. We demonstrated that accumulation of cholesterol in late endosomes/lysosomes induced bydrug treatment or siRNA knock-down of the cholesterol transporting NPC1 protein increases the degradation rate of PrPSc.On the other hand, cellular cholesterol metabolism is modulatedby prion infection. Highly controlled microarray studies revealedan up-regulation of genes involved in cholesterol metabolism inprion-infected neuronal cell lines and primary neurons, resultingin elevated levels of free cholesterol.Our current research focuses on investigating why prioninfection induces cholesterol synthesis, and what the consequences of abnormal cholesterol levels are for neuronal cells. Wehave addressed these questions by analysing the response of prioninfected cells to regulators of cholesterol synthesis. Our data indicate that prion infected cells do not respond with transcriptionalregulation of genes involved in cholesterol synthesis to treatment with certain drugs, indicating sequestration of cholesterol.Furthermore, we have studied the distribution of marker proteinsbetween lipid raft and non-lipid raft domains, and found a redistribution of the endosomal transmembrane protein NPC-1to lipid raft domains in prion infected cells. Analysis of themembrane association of selected rab proteins involved in endosomal vesicle trafficking indicate an interference of prion infection with lysosomal maturation.In summary, we suggest that prion infection leads to an increaseof cellular cholesterol levels and, as a consequence, interferes withlate endosomal vesicle trafficking in order to escape lysosomal degradation. This interference with host cell metabolism may enableand sustain stable prion propagation in neuronal cells.

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Contributing Institute(s):

1. Prion Cell Biology (AG Vorberg)

Research Program(s):

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

Appears in the scientific report 2014

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