Prion infection impairs lysosomal degradation capacity by interfering with rab7 membrane attachment in neuronal cells.

Su Yeon Shim,Sampson Law,Srinivasarao Karri,Sabine Gilch,Hermann M Schatzl

doi:10.1038/srep21658

Abstract

Prions are proteinaceous infectious particles which cause fatal neurodegenerative disorders in humans and animals. They consist of a mostly β-sheeted aggregated isoform (PrPSc) of the cellular prion protein (PrPc). Prions replicate autocatalytically in neurons and other cell types by inducing conformational conversion of PrPc into PrPSc. Within neurons, PrPSc accumulates at the plasma membrane and in vesicles of the endocytic pathway. To better understand the mechanisms underlying neuronal dysfunction and death it is critical to know the impact of PrPSc accumulation on cellular pathways. We have investigated the effects of prion infection on endo-lysosomal transport. Our study demonstrates that prion infection interferes with rab7 membrane association. Consequently, lysosomal maturation and degradation are impaired. Our findings indicate a mechanism induced by prion infection that supports stable prion replication. We suggest modulation of endo-lysosomal vesicle trafficking and enhancement of lysosomal maturation as novel targets for the treatment of prion diseases.

Highlights

Prions are proteinaceous infectious particles which cause fatal neurodegenerative disorders in humans and animals
We compared levels of rab[7] which is a late endosomal rab protein, rab[9] which mediates vesicle shuttling between the trans-Golgi network (TGN) and late endosomes, and rab[11] which localizes to recycling endosomes[23]
We used homologous cells cured of prion infections by treatment with pentosan polysulfate (PPS), a substance known to interfere with PrPSc propagation[29], or with glivec, which increases the degradation rate of PrPSc 30

Summary

Introduction

Prions are proteinaceous infectious particles which cause fatal neurodegenerative disorders in humans and animals They consist of a mostly β-sheeted aggregated isoform (PrPSc) of the cellular prion protein (PrPc). Prions replicate autocatalytically in neurons and other cell types by inducing conformational conversion of PrPc into PrPSc. Within neurons, PrPSc accumulates at the plasma membrane and in vesicles of the endocytic pathway. Our study demonstrates that prion infection interferes with rab[7] membrane association. Rab proteins comprise a large family of small GTPases which are localized to distinct intracellular membranes and regulate vesicle trafficking. They switch between an inactive, GDP-bound cytosolic state and an active, GTP-bound membrane associated state.

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