BCL-2 counteracts Doppel-induced apoptosis of prion-protein-deficient Purkinje cells in the Ngsk Prnp(0/0) mouse.
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 Prnp(0/0) (NP(0/0)) mouse. In view of cellular prion protein (PrP(c)) 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 NP(0/0)-Hu-bcl-2 double mutant mice overexpressing human BCL-2 (Hu-bcl-2). Quantitative analysis showed that significantly more PCs survived in NP(0/0)-Hu-bcl-2 double mutants compared with the NP(0/0) 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 NP(0/0) 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 NP(0/0) PCs by Hu-bcl-2 expression was similar to that observed in NP(0/0):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 PrP(c) deficiency by rescuing PCs from Dpl-induced death suggests that the BCL-2-like property of PrP(c) may impair Dpl-like neurotoxic pathways in wild-type neurons.
Heitz
S
S
Département Neurotransmission et Sécrétion Neuroendocrine, UMR7168-LC2 CNRS, France. heitz@neurochem.u-strasbg.fr
Gautheron
V
V
Lutz
Y
Y
Rodeau
J-L
JL
Zanjani
H S
HS
Sugihara
I
I
Bombarde
G
G
Richard
F
F
Fuchs
J-P
JP
Vogel
M W
MW
Mariani
J
J
Bailly
Y
Y
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D002531:Cerebellum / Q000166:cytology; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011328:Prions / Q000235:genetics* / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011689:Purkinje Cells / Q000187:drug effects*
D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein; C501125:PRND protein, human; D011328:Prions; D019253:Proto-Oncogene Proteins c-bcl-2; D005634:Fructose-Bisphosphate Aldolase