Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

FP5

PRP AND NEURODEGENER Berichtzusammenfassung

Project ID: QLG3-CT-2001-02353
Gefördert unter: FP5-LIFE QUALITY
Land: Germany

Signal transduction pathways mediated by PrP: Cis- and trans-interactions between PrP and NCAM are important for NCAM stabilization in lipid rafts 2

Cis- and trans-interactions between PrP and NCAM are important for NCAM stabilization in lipid rafts

Two distinct types of interaction between PrP and NCAM could account for the observed phenomena. PrP could stabilise NCAM in lipid rafts by cis-interaction, i.e. both molecules associate in the plasma membrane of the same neuron. To analyse the cis-interaction in lipid rafts, we estimated the amount of detergent insoluble NCAM in PrP+/+ and PrP-/- cultured hippocampal neurons. Only neurons without contacts were evaluated to assure that only cis-interactions were analysed. PrP-/- neurons extracted with cold Triton X-100 showed lower NCAM labelling intensity in NCAM clusters and along neurites when compared to PrP+/+ neurons, indicating a reduction of NCAM in lipid rafts. This reduction was not due to a decrease in expression of NCAM in PrP-/- neurons, since the mean labelling intensity of NCAM along neurites of non-extracted neurons was increased in PrP-/- neurons, in accordance with our biochemical data.

We conclude that cis-interactions between NCAM and PrP are important for stabilisation of NCAM in lipid rafts. PrP could also induce redistribution of NCAM to lipid rafts by trans-interaction, i.e. NCAM binds to PrP on adjacent cells. To analyse the role of a trans-interaction between NCAM and PrP, we applied soluble PrP-Fc to neurons from PrP-/- mice to evaluate the redistribution of NCAM to lipid rafts in absence of NCAM-to-PrP cis-interaction. Application of PrP-Fc increased the amount of detergent insoluble NCAM in NCAM clusters and along neurites of PrP-/- neurons. Since increase of NCAM levels in lipid rafts after application of PrP-Fc suggested a PrP-Fc induced redistribution of NCAM to lipid rafts, we measured the association of NCAM with lipid rafts in response to PrP-Fc application in PrP+/+ neurons using the PI(4,5)P2 raft marker (Niethammer et al., 2002). Amounts of PI(4,5)P2 in detergent insoluble NCAM clusters were increased after PrP-Fc application, indicating that PrP-Fc redistributed NCAM to lipid rafts. As for PrP-/- neurons, application of PrP-Fc to PrP+/+ neurons increased levels of detergent insoluble NCAM in NCAM clusters and along neurites. We conclude that trans-interaction of PrP with NCAM induces redistribution of NCAM to lipid rafts.

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