Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, 04023-062 São Paulo, Brazil.
Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13147-52. doi: 10.1073/pnas.1000784107. Epub 2010 Jul 6.
Transmissible spongiform encephalopathies are fatal neurodegenerative diseases caused by the conversion of prion protein (PrP(C)) into an infectious isoform (PrP(Sc)). How this event leads to pathology is not fully understood. Here we demonstrate that protein synthesis in neurons is enhanced via PrP(C) interaction with stress-inducible protein 1 (STI1). We also show that neuroprotection and neuritogenesis mediated by PrP(C)-STI1 engagement are dependent upon the increased protein synthesis mediated by PI3K-mTOR signaling. Strikingly, the translational stimulation mediated by PrP(C)-STI1 binding is corrupted in neuronal cell lines persistently infected with PrP(Sc), as well as in primary cultured hippocampal neurons acutely exposed to PrP(Sc). Consistent with this, high levels of eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation were found in PrP(Sc)-infected cells and in neurons acutely exposed to PrP(Sc). These data indicate that modulation of protein synthesis is critical for PrP(C)-STI1 neurotrophic functions, and point to the impairment of this process during PrP(Sc) infection as a possible contributor to neurodegeneration.
传染性海绵状脑病是由朊病毒蛋白（PrP(C)）转化为传染性异构体（PrP(Sc)）引起的致命神经退行性疾病。这一事件如何导致病理学尚不完全清楚。在这里，我们证明了神经元中的蛋白质合成是通过 PrP(C)与应激诱导蛋白 1（STI1）的相互作用增强的。我们还表明，PrP(C)-STI1 结合介导的神经保护和神经突生成依赖于 PI3K-mTOR 信号介导的增加的蛋白质合成。引人注目的是，在持续感染 PrP(Sc)的神经元细胞系以及急性暴露于 PrP(Sc)的原代培养海马神经元中，PrP(C)-STI1 结合介导的翻译刺激被破坏。与此一致，在 PrP(Sc)感染的细胞和急性暴露于 PrP(Sc)的神经元中发现了高水平的真核翻译起始因子 2alpha(eIF2alpha)磷酸化。这些数据表明蛋白质合成的调节对于 PrP(C)-STI1 的神经营养功能至关重要，并指出在 PrP(Sc)感染期间该过程的受损可能是神经退行性变的一个可能原因。
