BCL-2 counteracts doppel-induced apoptosis of prion-protein-deficient Purkinje cells in the Ngsk Prnp0/0 mouse
BCL-2 counteracts doppel-induced apoptosis of prion-protein-deficient Purkinje cells in the Ngsk Prnp0/0 mouse
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DOI：
10.1002/dneu.20555
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发表时间：
2008-02-15
影响因子：
3
通讯作者：
Bailly, Y.
中科院分区：
文献类型：
--
作者：
Heitz, S.;Gautheron, V.;Bailly, Y.
最近发现促凋亡因子Bax参与了神经毒性蛋白多普利(DPL)对PrNP(0/0)(NP0/0)小鼠的促凋亡作用。鉴于PrPc与bcl2一样具有对抗DPL神经毒性和促进神经元存活的能力，我们通过研究高表达人bcl2的NP0/0-Hu-bcl2双突变小鼠(hU-bcl2)衰老过程中PC死亡的进展，探讨了抗凋亡因子bcl2对DPL神经毒性的影响。定量分析表明，与NP0/0突变体相比，NP0/0-Hu-bcl2双突变体中的PC存活数量显著增加。然而，PC的数量仍然低于野生型水平和在Hu-bcl2突变体中观察到的PC数量的增加。在NP0/0突变体中，DPL诱导的PC死亡优先发生在小脑皮质醛缩酶C阴性的矢状面旁隔区。双重突变体中HU-BCL-2的表达使胶质细胞的激活完全消失，提示慢性炎症是DPL诱导的PC死亡的间接结果。这种对NP0/0PC的部分修复作用与在缺失bax的NP0/0：bax(-/-)双突变体中观察到的相似。综上所述，这些数据有力地支持了bcl2家族依赖的凋亡通路参与了DPL的神经毒性。Bcl-2通过从DPL诱导的死亡中拯救PC来弥补PrPc缺乏的能力表明，PrPc的bcl2样属性可能会损害野生型神经元中DPL样神经毒性通路。(C)2007年威利期刊公司。
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) (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. (C) 2007 Wiley Periodicals, Inc.