NR AORC
AU Carimalo,J.; Arbez,N.; Boukhtouche,F.; Lemaigre-Dubreuil,Y.; Brugg,B.; Miquel,M.C.
TI Crucial role of the JNK-c-jun pathway in the early events of neuronal apoptosis induced by hPrP106-126
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - PG-29
PT Konferenz-Poster
AB
Prion diseases are neurodegenerative pathologies characterized by the accumulation in the brain of a protease-resistant form of the prion protein PrPc, named PrPsc. Although apoptosis has been demonstrated to occur, the sequence of events involved in neuronal death is not yet known. Previous studies have shown that a synthetic peptide homologous to residues 106-126 of the human PrP (hPrP106 126) maintains many PrPsc characteristics, i.e. the ability to form amyloid structures and to induce neuronal apoptosis ex vivo. We have thus studied the intracellular events triggered by this peptide during the early phase of apoptosis in primary cultures of cortical neurons.
In our model, the latency phase is achieved after 8 hrs upon exposure to the agregated hPrP106 126 (80µM). Cell death occurs at 50% after 16 hrs and at 70% within 24hrs with the nuclear characteristics of apoptosis. Reactive oxygen species were detected after 3 hrs and the activation of caspase-3 after 8 hrs of treatment.
Along with the traditional morphological changes after 16-24 hrs (dendritic retraction and fragmentation), transfection by the Green Fluorescent Protein showed earlier alterations of dendritic morphology which could be characteristic of hPrP106 126 induced events and are under further study.
Finally, we are reporting a peak of c-Jun-N-terminal kinase (JNK) phosphorylation after 8 hrs along with the activation of the nuclear c-jun transcription factor. Pharmacological inhibition of JNK by SP600125 prevents neuronal death by 70%.
In summary, we have demonstrated for the first time that the JNK-c-jun pathway plays a critical role in neuronal apoptosis induced by hPrP106-126. The fact that neuronal death is largely prevented by pharmacological blockade of this early phase opens new therapeutical prospects for PrPsc-based pathologies.
AD J. Carimalo, N. Arbez, F. Boukhtouche, Y. Lemaigre-Dubreuil, B. Brugg, M.C. Miquel, CNRS UMR 7102 Université Paris 6, France
SP englisch
PO Deutschland