Wadsworth Jonathan D F, Joiner Susan, Linehan Jacqueline M, Cooper Sharon, Powell Caroline, Mallinson Gary, Buckell Jennifer, Gowland Ian, Asante Emmanuel A, Budka Herbert, Brandner Sebastian, Collinge John
MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery Queen Square, London, UK.
Brain. 2006 Jun;129(Pt 6):1557-69. doi: 10.1093/brain/awl076. Epub 2006 Apr 5.
Inherited prion diseases are caused by PRNP coding mutations and display marked phenotypic heterogeneity within families segregating the same pathogenic mutation. A proline-to-leucine substitution at prion protein (PrP) residue 102 (P102L), classically associated with the Gerstmann-Sträussler-Scheinker (GSS) phenotype, also shows marked clinical and pathological heterogeneity, including patients with a Creutzfeldt-Jakob disease (CJD) phenotype. To date, this heterogeneity has been attributed to temporal and spatial variance in the propagation of distinct protease-resistant (PrP(Sc)) isoforms of mutant PrP. Here, using a monoclonal antibody that recognizes wild-type PrP, but not PrP 102L, we reveal a spectrum of involvement of wild-type PrP(Sc) in P102L individuals. PrP(Sc) isoforms derived from wild-type and mutant PrP are distinct both from each other and from those seen in sporadic and acquired CJD. Such differential propagation of disease-related isoforms of wild-type PrP and PrP 102L provides a molecular mechanism for generation of the multiple clinicopathological phenotypes seen in inherited prion disease.
遗传性朊病毒病由PRNP编码突变引起，在携带相同致病突变的家系中表现出明显的表型异质性。朊病毒蛋白（PrP）第102位残基（P102L）由脯氨酸替换为亮氨酸，传统上与格斯特曼-施特劳斯勒-谢inker综合征（GSS）表型相关，也表现出明显的临床和病理异质性，包括克雅氏病（CJD）表型的患者。迄今为止，这种异质性归因于突变型PrP不同蛋白酶抗性（PrP(Sc)）异构体传播的时间和空间差异。在这里，我们使用一种识别野生型PrP但不识别PrP 102L的单克隆抗体，揭示了野生型PrP(Sc)在P102L个体中的一系列参与情况。源自野生型和突变型PrP的PrP(Sc)异构体彼此不同，也与散发性和获得性CJD中所见的异构体不同。野生型PrP和PrP 102L疾病相关异构体的这种差异传播为遗传性朊病毒病中所见的多种临床病理表型的产生提供了分子机制。
