Dataset Information

Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide.

ABSTRACT:

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.

SUBMITTER: Wilson R

PROVIDER: S-EPMC2131757 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Publications

Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide.

Wilson Rona R Bate Clive C Boshuizen Ronald R Williams Alun A Brewer James J

BMC neuroscience 20071122

<h4>Background</h4>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.<h4>Results</h4>Fluorescence microscopy and cell fractionation techniques showed that MoPrP105-132 co- ...[more]

PMID: 18034899

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Dataset Information

Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide.

Background

Results

Conclusion

Publications

Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide.

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