BCL‐2 counteracts Doppel‐induced apoptosis of prion‐protein‐deficient Purkinje cells in the Ngsk Prnp0/0 mouse

• Published in: Developmental neurobiology (Hoboken, N.J.) Vol. 68; no. 3; pp. 332 - 348
• Main Authors: Heitz, S., Gautheron, V., Lutz, Y., Rodeau, J.‐L., Zanjani, H.S., Sugihara, I., Bombarde, G., Richard, F., Fuchs, J.‐P., Vogel, M.W., Mariani, J., Bailly, Y.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.02.2008
• Subjects: apoptosis; BCL‐2; Doppel; neurodegeneration; prion protein; Purkinje cell
• ISSN: 1932-8451; 1932-846X
• DOI: 10.1002/dneu.20555

The pro‐apoptotic factor BAX has recently been shown to contribute to Purkinje cell (PC) apoptosis induced by the neurotoxic prion‐like protein Doppel (Dpl) in the prion‐protein‐deficient Ngsk Prnp0/0 (NP0/0) mouse. In view of cellular prion protein (PrPc) ability to counteract Dpl neurotoxicity and favor neuronal survival like BCL‐2, we investigated the effects of the anti‐apoptotic factor BCL‐2 on Dpl neurotoxicity by studying the progression of PC death in aging NP0/0‐Hu‐bcl‐2 double mutant mice overexpressing human BCL‐2 (Hu‐bcl‐2). Quantitative analysis showed that significantly more PCs survived in NP0/0‐Hu‐bcl‐2 double mutants compared with the NP0/0 mutants. However, number of PCs remained inferior to wild‐type levels and to the increased number of PCs observed in Hu‐bcl‐2 mutants. In the NP0/0 mutants, Dpl‐induced PC death occurred preferentially in the aldolase C‐negative parasagittal compartments of the cerebellar cortex. Activation of glial cells exclusively in these compartments, which was abolished by the expression of Hu‐bcl‐2 in the double mutants, suggested that chronic inflammation is an indirect consequence of Dpl‐induced PC death. This partial rescue of NP0/0 PCs by Hu‐bcl‐2 expression was similar to that observed in NP0/0:Bax−/− double mutants with bax deletion. Taken together, these data strongly support the involvement of BCL‐2 family‐dependent apoptotic pathways in Dpl neurotoxicity. The capacity of BCL‐2 to compensate PrPc deficiency by rescuing PCs from Dpl‐induced death suggests that the BCL‐2‐like property of PrPc may impair Dpl‐like neurotoxic pathways in wild‐type neurons. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2008