A point mutation in GPI-attachment signal peptide accelerates the development of prion disease
A point mutation in GPI-attachment signal peptide accelerates the development of prion disease
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DOI：
10.1007/s00401-023-02553-5
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发表时间：
2023-03
影响因子：
12.7
通讯作者：
A. Kobayashi;T. Hirata;Taishi Shimazaki;Yoshiko Munesue;K. Aoshima;Takashi Kimura;J. Nio-Kobayashi;R. Hasebe;Atsuko Takeuchi;Y. Matsuura;S. Kusumi;D. Koga;Y. Iwasaki;Taroh Kinoshita;S. Mohri;T. Kitamoto
中科院分区：
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作者：
A. Kobayashi;T. Hirata;Taishi Shimazaki;Yoshiko Munesue;K. Aoshima;Takashi Kimura;J. Nio-Kobayashi;R. Hasebe;Atsuko Takeuchi;Y. Matsuura;S. Kusumi;D. Koga;Y. Iwasaki;Taroh Kinoshita;S. Mohri;T. Kitamoto
朊病毒蛋白基因第232位密码子(M232R)处的蛋氨酸错义变体为精氨酸，占日本遗传性朊病毒病患者的15%左右。然而，M232R 替代对诱发朊病毒病的致病作用仍然难以捉摸，因为 M232R 患者通常没有家族史。此外，M232R患者的临床病理表型与散发性克雅氏病患者没有区别。此外，M232R 取代位于糖基磷脂酰肌醇 (GPI) 附着信号肽中，该信号肽在朊病毒蛋白成熟过程中被裂解。因此，有人认为M232R取代可能是一种罕见的多态性，而不是致病性突变。为了揭示朊病毒蛋白GPI连接信号肽中M232R取代在朊病毒病发病机制中的作用，我们构建了表达带有M232R的人朊病毒蛋白的小鼠模型，并研究了对朊病毒病的易感性。 M232R 取代以朊病毒株依赖性方式加速朊病毒疾病的发展，而不影响朊病毒株特异性的组织病理学和生化特征。 M232R 取代没有改变 GPI 的附着，也没有改变 GPI 附着位点。相反，该取代通过降低GPI附着信号肽的疏水性改变了朊病毒蛋白的内质网易位途径，导致朊病毒蛋白的N-连接糖基化和GPI糖基化减少。据我们所知，这是首次证明 GPI 连接信号肽点突变与疾病发展之间的直接关系。
A missense variant from methionine to arginine at codon 232 (M232R) of the prion protein gene accounts for ~ 15% of Japanese patients with genetic prion diseases. However, pathogenic roles of the M232R substitution for the induction of prion disease have remained elusive because family history is usually absent in patients with M232R. In addition, the clinicopathologic phenotypes of patients with M232R are indistinguishable from those of sporadic Creutzfeldt-Jakob disease patients. Furthermore, the M232R substitution is located in the glycosylphosphatidylinositol (GPI)-attachment signal peptide that is cleaved off during the maturation of prion proteins. Therefore, there has been an argument that the M232R substitution might be an uncommon polymorphism rather than a pathogenic mutation. To unveil the role of the M232R substitution in the GPI-attachment signal peptide of prion protein in the pathogenesis of prion disease, here we generated a mouse model expressing human prion proteins with M232R and investigated the susceptibility to prion disease. The M232R substitution accelerates the development of prion disease in a prion strain-dependent manner, without affecting prion strain-specific histopathologic and biochemical features. The M232R substitution did not alter the attachment of GPI nor GPI-attachment site. Instead, the substitution altered endoplasmic reticulum translocation pathway of prion proteins by reducing the hydrophobicity of the GPI-attachment signal peptide, resulting in the reduction ofN-linked glycosylation and GPI glycosylation of prion proteins. To the best of our knowledge, this is the first time to show a direct relationship between a point mutation in the GPI-attachment signal peptide and the development of disease.