Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide

Wilson, R., Bate, C., Boshuizen, R., Williams, A. and Brewer, J. (2007) Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide. BMC Neuroscience, 8, 99. (doi: 10.1186/1471-2202-8-99) (PMID:18034899) (PMCID:PMC2131757)

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Background: Neurotoxic peptides derived from the protease-resistant core of the prion protein are used to model the pathogenesis of prion diseases. The current study characterised the ingestion, internalization and intracellular trafficking of a neurotoxic peptide containing amino acids 105–132 of the murine prion protein (MoPrP105-132) in neuroblastoma cells and primary cortical neurons. Results: Fluorescence microscopy and cell fractionation techniques showed that MoPrP105-132 co-localised with lipid raft markers (cholera toxin and caveolin-1) and trafficked intracellularly within lipid rafts. This trafficking followed a non-classical endosomal pathway delivering peptide to the Golgi and ER, avoiding classical endosomal trafficking via early endosomes to lysosomes. Fluorescence resonance energy transfer analysis demonstrated close interactions of MoPrP105-132 with cytoplasmic phospholipase A2 (cPLA2) and cyclo-oxygenase-1 (COX-1), enzymes implicated in the neurotoxicity of prions. Treatment with squalestatin reduced neuronal cholesterol levels and caused the redistribution of MoPrP105-132 out of lipid rafts. In squalestatin-treated cells, MoPrP105-132 was rerouted away from the Golgi/ER into degradative lysosomes. Squalestatin treatment also reduced the association between MoPrP105-132 and cPLA2/COX-1. Conclusion: As the observed shift in peptide trafficking was accompanied by increased cell survival these studies suggest that the neurotoxicity of this PrP peptide is dependent on trafficking to specific organelles where it activates specific signal transduction pathways.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Brewer, Professor James
Authors: Wilson, R., Bate, C., Boshuizen, R., Williams, A., and Brewer, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:BMC Neuroscience
Publisher:Biomed Central
ISSN (Online):1471-2202
Copyright Holders:Copyright © 2007 Wilson et al.
First Published:First published in BMC Neuroscience 8: 99
Publisher Policy:Reproduced under a Creative Commons License

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