Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani", Università di Pavia, Pavia, Italy.
J Chem Neuroanat. 2012 Dec;46(1-2):19-29. doi: 10.1016/j.jchemneu.2012.09.003. Epub 2012 Sep 24.
Programmed cell death is regulated by prototypes of a large family of Bcl-2-like proteins such as Bax and Bcl-2. A neuroprotective role for cellular prion protein (PrPc) on programmed cell death has been reported, although the cytosolic accumulation of PrPc correlates with toxicity and death of some neurons by apoptosis. In order to understand the signalling function of PrPc in promoting survival or suppressing cell death, we analyzed the expression and co-localization of PrPc, Bax and Bcl-2 proteins in the developing cerebellum of rats treated at PD10 (postnatal day 10) with the chemotherapeutic drug cisplatin (cisPt) or the new platinum (Pt) compound [Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS). Differences in the expression of PrPc, Bax and Bcl-2 were found in proliferating cells and immature Purkinje neurons. One day after administration (PD11), cisPt markedly increased the apoptosis of the proliferating cells of the EGL (external granular layer); at the same time, several apoptotic bodies with strong Bax immunoreactivity were noticed. After PtAcacDMS, changes in PrPc and apoptotic proteins, with respect to the controls, were found but Bax immunopositive apoptotic bodies were not detectable, which could mean that apoptotic cell death of proliferating cells is preserved. Co-localization was clearly detected in the Purkinje cell population and may explain better the mechanisms by which PrPc and the apoptotic proteins function, and particularly the role of PrPc. Considering the reactivity of Purkinje neurons to these proteins at PD11 and Pd17, at least PrPc expression increased after cisPt and PtAcacDMS treatments or, if PrPc decreased, balanced itself with Bcl-2. The noteworthiness of this finding is that it emphasizes that most of the post-mitotic Purkinje cells need to be rescued, otherwise they undergo degeneration and are not replaced. Based on the effects of both Pt compounds on Purkinje cell differentiation, it should be emphasized that PrPc, together with the synergistic action of the co-localized anti-apoptotic protein, acts as a neuroprotective protein countering cytotoxicity in the postnatal critical phases of cerebellum development.
细胞程序性死亡受 Bax 和 Bcl-2 等 Bcl-2 样蛋白大家族原型的调控。有报道称，细胞朊蛋白 (PrPc) 在程序性细胞死亡中具有神经保护作用，尽管 PrPc 的细胞质积累与某些神经元通过细胞凋亡而产生的毒性和死亡相关。为了了解 PrPc 在促进存活或抑制细胞死亡中的信号转导功能，我们分析了在 PD10（出生后第 10 天）用化疗药物顺铂 (cisPt) 或新型铂 (Pt) 化合物 [Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS) 处理的大鼠发育小脑组织中 PrPc、Bax 和 Bcl-2 蛋白的表达和共定位。在增殖细胞和未成熟的浦肯野神经元中发现 PrPc、Bax 和 Bcl-2 的表达存在差异。给药后一天 (PD11)，cisPt 明显增加了 EGL（外颗粒层）中增殖细胞的凋亡；同时，观察到几个带有强烈 Bax 免疫反应性的凋亡小体。与对照组相比，在用 PtAcacDMS 处理后，PrPc 和凋亡蛋白发生了变化，但未检测到 Bax 免疫阳性的凋亡小体，这可能意味着增殖细胞的凋亡性死亡得以保留。在浦肯野细胞群体中清楚地检测到共定位，这可以更好地解释 PrPc 和凋亡蛋白的作用机制，特别是 PrPc 的作用机制。考虑到 PD11 和 PD17 时浦肯野神经元对这些蛋白质的反应性，至少在 cisPt 和 PtAcacDMS 处理后，PrPc 的表达增加，或者如果 PrPc 减少，它与 Bcl-2 平衡。这一发现的重要性在于，它强调了大多数有丝分裂后浦肯野细胞需要被挽救，否则它们会发生退化而无法替代。基于这两种 Pt 化合物对浦肯野细胞分化的影响，应该强调的是，PrPc 与共定位的抗凋亡蛋白的协同作用一起，作为一种神经保护蛋白，在小脑发育的产后关键阶段对抗细胞毒性。
