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Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide

Overview of attention for article published in BMC Neuroscience, November 2007
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Title
Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide
Published in
BMC Neuroscience, November 2007
DOI 10.1186/1471-2202-8-99
Pubmed ID
Authors

Rona Wilson, Clive Bate, Ronald Boshuizen, Alun Williams, James Brewer

Abstract

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. 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. 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.

Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 32 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Chile 1 3%
Netherlands 1 3%
France 1 3%
Unknown 29 91%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 7 22%
Student > Ph. D. Student 6 19%
Student > Doctoral Student 5 16%
Researcher 4 13%
Professor 3 9%
Other 3 9%
Unknown 4 13%
Readers by discipline Count As %
Agricultural and Biological Sciences 13 41%
Biochemistry, Genetics and Molecular Biology 4 13%
Veterinary Science and Veterinary Medicine 3 9%
Medicine and Dentistry 2 6%
Engineering 2 6%
Other 4 13%
Unknown 4 13%