Coulpier Muriel, Messiaen Sébastien, Hamel Rodolphe, Fernández de Marco Mar, Lilin Thomas, Eloit Marc
UMR Virologie 1161 INRA-AFSSA-ENVA, Ecole Nationale Vétérinaire d'Alfort, 94704 Maisons-Alfort, France.
Neurobiol Dis. 2006 Sep;23(3):603-11. doi: 10.1016/j.nbd.2006.05.013. Epub 2006 Jul 18.
Neurodegeneration is a common neuropathological feature of prion diseases. Although evidence of apoptosis was found in natural and experimental prion diseases, the precise mechanisms by which neurons die are poorly understood. The pro-apoptotic BAX protein, a key factor of the mitochondrial pathway, plays a central role in the regulation of neuronal apoptosis. Recently, BAX was implicated in neuronal death in a transgenic model of inherited prion disease. Nevertheless, whether neurodegeneration occurs by similar mechanisms in other prion diseases remains unknown. Here, using mice knocked out for the Bax gene, we investigated BAX implication in neuronal death induced by a prion disease of infectious origin. A mouse-adapted prion strain of bovine spongiform encephalopathy (BSE) was inoculated intracerebrally into Bax-/- mice and their wild-type littermates. We found that Bax inactivation did not alter the development of the disease. Clinical illness was not prevented. PrP(res) deposition and astrogliosis occurred to the usual extent. Neuronal integrity was not maintained, and neurons in hippocampus and thalamus were not protected. These results demonstrated that BAX is not necessary for neuron death induced by the BSE strain. They suggest the existence of multiple molecular death pathways in prion diseases.
神经退行性变是朊病毒疾病常见的神经病理学特征。尽管在自然发生和实验性朊病毒疾病中发现了细胞凋亡的证据，但神经元死亡的确切机制仍知之甚少。促凋亡蛋白BAX是线粒体途径的关键因子，在神经元凋亡的调控中起核心作用。最近，在遗传性朊病毒疾病的转基因模型中，BAX与神经元死亡有关。然而，在其他朊病毒疾病中神经退行性变是否通过类似机制发生仍不清楚。在此，我们利用敲除Bax基因的小鼠，研究了BAX在传染性朊病毒疾病诱导的神经元死亡中的作用。将适应小鼠的牛海绵状脑病（BSE）朊病毒株脑内接种到Bax-/-小鼠及其野生型同窝小鼠体内。我们发现Bax失活并没有改变疾病的发展。临床疾病并未得到预防。PrP(res)沉积和星形胶质细胞增生的程度与往常一样。神经元完整性未得到维持，海马体和丘脑的神经元未受到保护。这些结果表明，BAX对于BSE毒株诱导的神经元死亡并非必需。它们提示朊病毒疾病中存在多种分子死亡途径。
