Zanusso Gianluigi, Ferrari Sergio, Benedetti Diego, Sbriccoli Marco, Rizzuto Nicola, Monaco Salvatore
Department of Neurological and Visual Science, Section of Clinical Neurology, University of Verona, Verona, Italy.
Ann N Y Acad Sci. 2009 Jul;1170:637-43. doi: 10.1111/j.1749-6632.2009.03905.x.
Prion diseases, or transmissible spongiform encephalopathies (TSEs), are mammalian neurodegenerative diseases that occur as sporadic, inherited, or iatrogenic forms. Human TSEs exhibit a wide spectrum of phenotypic variability, which is influenced by (1) the conformation of the pathologic prion protein, or PrP(Sc); (2) the polymorphic codon 129 of the prion protein gene (PRNP), involving synonymous or nonsynonymous expression of Met or Val; and (3) the site of formation or entry of the self-replicating PrP(Sc). Brain deposition of PrP(Sc) occurs in a phenotype-specific regional pattern, either as extracellular amyloid plaques and plaque-like aggregates, or as fine granular immunoreactivity at intracellular sites and presynaptic and postsynaptic locations, including dendrites. We previously demonstrated PrP(Sc) deposition in ciliated dendrites of olfactory sensory neurons in sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease. PrP(Sc) immunoreactivity was not limited to the olfactory neuroepithelium. But additionally involved the central olfactory pathway. More recently, we have found that the pathology of the olfactory pathway occurs early in the disease course, either in the myoclonic or classic sCJD or in the ataxic variant. Intriguingly, in the ataxic or cerebellar variant, mainly observed in patients with the Met/Val polymorphism (2) carrying PrP(Sc) type 2, olfactory involvement is accompanied by pathologic changes in the dorsal motor nucleus of the vagus and other brainstem nuclei. These findings suggest that different molecular events and distinct routes of PrP(Sc) spread contribute to the prominent heterogeneity of sCJD, conceivably providing support to the olfactory pathogenesis theory of neurodegenerative diseases.
朊病毒病，即传染性海绵状脑病（TSEs），是哺乳动物的神经退行性疾病，以散发性、遗传性或医源性形式出现。人类TSEs表现出广泛的表型变异性，这受到以下因素影响：（1）病理性朊病毒蛋白（PrP(Sc)）的构象；（2）朊病毒蛋白基因（PRNP）的多态密码子129，涉及甲硫氨酸（Met）或缬氨酸（Val）的同义或非同义表达；（3）自我复制的PrP(Sc)的形成或进入部位。PrP(Sc)在大脑中的沉积以表型特异性的区域模式发生，要么表现为细胞外淀粉样斑块和斑块样聚集体，要么表现为细胞内部位以及包括树突在内的突触前和突触后位置的细颗粒免疫反应性。我们之前在散发性克雅氏病（sCJD）（最常见的人类朊病毒病）的嗅觉感觉神经元的纤毛树突中证实了PrP(Sc)的沉积。PrP(Sc)免疫反应性不仅限于嗅神经上皮，还涉及中枢嗅觉通路。最近，我们发现嗅觉通路的病理变化在疾病进程早期就会出现，无论是在肌阵挛性或经典型sCJD中，还是在共济失调变异型中。有趣的是，在主要在携带2型PrP(Sc)的甲硫氨酸/缬氨酸多态性（2）患者中观察到的共济失调或小脑变异型中，嗅觉受累伴随着迷走神经背运动核和其他脑干核的病理变化。这些发现表明，不同的分子事件和PrP(Sc)传播的不同途径导致了sCJD显著的异质性，这可能为神经退行性疾病的嗅觉发病机制理论提供支持。
