Medrano Andrea Z, Barmada Sami J, Biasini Emiliano, Harris David A
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Neurobiol Dis. 2008 Jul;31(1):20-32. doi: 10.1016/j.nbd.2008.03.006. Epub 2008 Apr 7.
A nine-octapeptide insertional mutation in the prion protein (PrP) causes a fatal neurodegenerative disorder in both humans and transgenic mice. To determine the precise cellular localization of this mutant PrP (designated PG14), we have generated transgenic mice expressing PG14-EGFP, a fluorescent fusion protein that can be directly visualized in vivo. Tg(PG14-EGFP) mice develop an ataxic neurological illness characterized by astrogliosis, PrP aggregation, and accumulation of a partially protease-resistant form of the mutant PrP. Strikingly, PG14-EGFP forms numerous fluorescent aggregates in the neuropil and white matter of multiple brain regions. These aggregates are particularly prominent along axonal tracts in both brain and peripheral nerve, and similar intracellular deposits are visible along the processes of cultured neurons. Our results reveal intra-axonal aggregates of a mutant PrP, which could contribute to the pathogenesis of familial prion disease by disrupting axonal transport.
朊病毒蛋白（PrP）中的一个九肽插入突变在人类和转基因小鼠中都会引发致命的神经退行性疾病。为了确定这种突变型PrP（命名为PG14）的确切细胞定位，我们构建了表达PG14-EGFP的转基因小鼠，PG14-EGFP是一种荧光融合蛋白，可在体内直接观察到。Tg(PG14-EGFP)小鼠会发展出一种共济失调性神经疾病，其特征为星形胶质细胞增生、PrP聚集以及突变型PrP部分抗蛋白酶形式的积累。令人惊讶的是，PG14-EGFP在多个脑区的神经毡和白质中形成了大量荧光聚集体。这些聚集体在脑和外周神经的轴突束中尤为突出，并且在培养神经元的突起上也可见类似的细胞内沉积物。我们的结果揭示了突变型PrP的轴突内聚集体，这可能通过破坏轴突运输而导致家族性朊病毒病的发病机制。
