Crozet Carole, Vézilier Julien, Delfieu Virginie, Nishimura Takuya, Onodera Takashi, Casanova Danielle, Lehmann Sylvain, Béranger Florence
Institut de Génétique Humaine, UPR CNRS1142, 141 Rue de la Cardonille, 34396 Montpellier cedex 5, France.
Mol Cell Neurosci. 2006 Aug;32(4):315-23. doi: 10.1016/j.mcn.2006.05.004. Epub 2006 Jun 27.
The mechanisms of prion-induced neurological dysfunction observed in prion diseases are poorly understood. Transgenic mice expressing a truncated form of the prion protein (23-230 PrP) acquire cerebellar degeneration (Ma and Lindquist, Science, 2002). To decipher the mechanisms of neurodegeneration induced by 23-230 PrP, we established inducible cell lines expressing this truncated form of PrP. We found that 23-230 PrP, expected to be cytosolic, accumulated mostly in the nucleus of the cells and was not cytotoxic. Nuclear localization of this mutant form of PrP is independent of its predicted nuclear localization signals. In contrast to what we previously described for PrPSc, nuclear accumulation of 23-230 PrP does not require a functional microtubule network. We observed that 23-230 PrP interacts with chromatin in vivo, as already described for recombinant PrP and for PrPSc. Our data demonstrate that the 23-230 PrP model does not reflect the situation of a cytosolic PrP but could represent a very useful tool to understand the consequences of the accumulation of the prion protein in the nucleus.
在朊病毒疾病中观察到的朊病毒诱导神经功能障碍的机制尚不清楚。表达截短形式朊病毒蛋白（23 - 230 PrP）的转基因小鼠会出现小脑变性（Ma和Lindquist，《科学》，2002年）。为了解析由23 - 230 PrP诱导的神经变性机制，我们建立了表达这种截短形式PrP的诱导细胞系。我们发现，预期定位于胞质的23 - 230 PrP大多积聚在细胞核中，且无细胞毒性。这种突变形式的PrP的核定位与其预测的核定位信号无关。与我们之前对PrPSc的描述不同，23 - 230 PrP的核积聚不需要功能性微管网络。我们观察到，23 - 230 PrP在体内与染色质相互作用，这与重组PrP和PrPSc的情况相同。我们的数据表明，23 - 230 PrP模型并不反映胞质PrP的情况，但可能是理解朊病毒蛋白在细胞核中积聚后果的非常有用的工具。
