Lewis Victoria, Hill Andrew F, Haigh Cathryn L, Klug Genevieve M, Masters Colin L, Lawson Victoria A, Collins Steven J
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
J Neuropathol Exp Neurol. 2009 Oct;68(10):1125-35. doi: 10.1097/NEN.0b013e3181b96981.
Prion disease pathogenesis is linked to the cell-associated propagation of misfolded protease-resistant conformers (PrP) of the normal cellular prion protein (PrP). Ongoing PrP expression is the only known absolute requirement for successful prion disease transmission and PrP propagation. Further typifying prion disease is selective neuronal dysfunction and loss, although the precise mechanisms underlying this are undefined. We utilized a single prion strain (M1000) and a range of neuronal and nonneuronal, PrP endogenously expressing and transgenically modified overexpressing cell lines, to evaluate whether PrP glycosylation patterns or constitutive N-terminal cleavage events may be determinants of sustained PrP propagation. Our data demonstrates that relative proportions of full-length and C1 truncated PrP are the most important characteristics influencing susceptibility to sustained M1000 prion infection, supporting PrP alpha-cleavage as a protective event, which may contribute to the selective neuronal vulnerability observed in vivo.
朊病毒病的发病机制与正常细胞朊病毒蛋白（PrP）的错误折叠且抗蛋白酶的构象异构体（PrP）在细胞中的传播有关。持续的PrP表达是朊病毒病成功传播和PrP增殖唯一已知的绝对必要条件。朊病毒病的另一个典型特征是选择性神经元功能障碍和丧失，尽管其确切机制尚不清楚。我们利用单一朊病毒株（M1000）以及一系列神经元和非神经元、内源性表达PrP和转基因修饰过表达的细胞系，来评估PrP糖基化模式或组成性N端切割事件是否可能是PrP持续增殖的决定因素。我们的数据表明，全长PrP和C1截短型PrP的相对比例是影响对持续M1000朊病毒感染易感性的最重要特征，支持PrP的α-切割作为一种保护事件，这可能导致体内观察到的选择性神经元易损性。
