Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein

Protein translocation into the endoplasmic reticulum is mediated by signal sequences that vary widely in primary structure. In vitro studies suggest that such signal sequence variations may correspond to subtly different functional properties. Whether comparable functional differences exist in vivo...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of cell biology 2010-02, Vol.188 (4), p.515-526
Main Authors: Rane, Neena S, Chakrabarti, Oishee, Feigenbaum, Lionel, Hegde, Ramanujan S
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Cricetinae
Gels
Humans
Huntington Disease - genetics
Huntington Disease - pathology
Membrane Proteins - metabolism
Membranes
Mice
Mice, Transgenic
Mutation
Mutation - genetics
Nerve Degeneration - pathology
Nervous system diseases
Neurodegeneration
Neurodegenerative diseases
Neurons
Pathogenesis
Phenotype
Phenotypes
Prions
Prions - biosynthesis
Prions - metabolism
Protein Sorting Signals
Protein Transport
Proteins
Rodents
Transgenes
Transgenic animals
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Protein translocation into the endoplasmic reticulum is mediated by signal sequences that vary widely in primary structure. In vitro studies suggest that such signal sequence variations may correspond to subtly different functional properties. Whether comparable functional differences exist in vivo and are of sufficient magnitude to impact organism physiology is unknown. Here, we investigate this issue by analyzing in transgenic mice the impact of signal sequence efficiency for mammalian prion protein (PrP). We find that replacement of the average efficiency signal sequence of PrP with more efficient signals rescues mice from neurodegeneration caused by otherwise pathogenic PrP mutants in a downstream hydrophobic domain (HD). This effect is explained by the demonstration that efficient signal sequence function precludes generation of a cytosolically exposed, disease-causing transmembrane form of PrP mediated by the HD mutants. Thus, signal sequences are functionally nonequivalent in vivo, with intrinsic inefficiency of the native PrP signal being required for pathogenesis of a subset of disease-causing PrP mutations.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200911115