title: Prion infection impairs lysosomal degradation capacity by interfering with rab7 membrane attachment in neuronal cells.
abstract: Prions are proteinaceous infectious particles which cause fatal neurodegenerative disorders in humans and animals. They consist of a mostly β-sheeted aggregated isoform (PrP(Sc)) of the cellular prion protein (PrP(c)). Prions replicate autocatalytically in neurons and other cell types by inducing conformational conversion of PrP(c) into PrP(Sc). Within neurons, PrP(Sc) 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 PrP(Sc) 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.
authors: Dept. of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.
authors: Su Yeon
authors: SY
authors: Shim
authors: Dept. of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.
authors: Srinivasarao
authors: S
authors: Karri
authors: Dept. of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.
authors: Sampson
authors: S
authors: Law
authors: Dept. of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.|Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors: Hermann M
authors: HM
authors: Schatzl
authors: Dept. of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.|Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors: Sabine
authors: S
authors: Gilch
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport; D022161:Transport Vesicles / Q000378:metabolism* / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D020691:rab GTP-Binding Proteins