Study on pathologic mechanism of wild or mutant prion protein gene.

最近的分子遗传学研究表明，人类朊蛋白（PrP）基因具有大量的多态性和突变。每种变体PrP似乎对应于一种不同类型的朊病毒疾病。在这个项目中，我们发现了6个新的PrP基因突变和3个插入突变。根据PrP在中枢神经系统的分布，将朊病毒疾病分为斑块型和非斑块型是有用的。变异型PrP（密码子102、密码子102/219、密码子105、密码子129缬氨酸、密码子145和插入多态性）属于斑块型朊病毒疾病，而野生型PrP（密码子129蛋氨酸）和变异型PrP（密码子180、密码子200和密码子232突变）属于非斑块型（突触型）。非斑块型朊病毒病表现为快速进行性痴呆、肌阵挛和周期性同步放电，病理表现为弥漫性灰质PrP积聚，包括突触结构。斑块型朊病毒病临床病程长，无肌阵挛和周期性同步放电，PrP主要积聚部位为细胞外PrP斑块。PrP沉积在中枢神经系统的分布影响着朊病毒疾病的临床和病理方面。因此，PrP积累可能在朊病毒疾病的发病机制中发挥核心作用。

Recent molecular genetic studies revealed that the human prion protein (PrP) gene has a large repertoire of polymorphisms and mutations. Each variant PrP seems to correspond to a distinct type of prion diseases. On this project, we found out 6 new mutations and 3 insertional mutations of PrP gene. It is useful to classify prion diseases into plaque type or non-plaque type, based on the distribution of PrP in the central nervous system. The variant PrP including codon 102, codon 102/219, codon 105, codon 129 Valine, codon 145 and insertional polymorphisms belong to the plaque type prion diseases, whereas the wild-type PrP (codon 129 Methionine) and the variants including codon 180, codon 200, and codon 232 mutations belong to the non-plaque type (synaptic type). The non-plaque type prion diseases showed a rapidly progressive dementia, myoclonus and periodic synchronous discharges in the electroencephalogram, and in the pathological findings diffuse gray matter PrP accumulations including the synaptic structures. The plaque type prion diseases showed a long clinical course without myoclonus and periodic synchronous discharges, and the major PrP accumulation sites were extracellular PrP plaques. The distribution of PrP deposits in the central nervous system influences the clinical and pathological aspects of prion diseases. Thus, PrP accumulations may play a central role in the pathogenesis of prion diseases.