Whatley Brandi R, Li Lian, Chin Lih-Shen
Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
Biochim Biophys Acta. 2008 Dec;1782(12):700-12. doi: 10.1016/j.bbadis.2008.08.006. Epub 2008 Aug 23.
Spongiform degeneration is characterized by vacuolation in nervous tissue accompanied by neuronal death and gliosis. Although spongiform degeneration is a hallmark of prion diseases, this pathology is also present in the brains of patients suffering from Alzheimer's disease, diffuse Lewy body disease, human immunodeficiency virus (HIV) infection, and Canavan's spongiform leukodystrophy. The shared outcome of spongiform degeneration in these diverse diseases suggests that common cellular mechanisms must underlie the processes of spongiform change and neurodegeneration in the central nervous system. Immunohistochemical analysis of brain tissues reveals increased ubiquitin immunoreactivity in and around areas of spongiform change, suggesting the involvement of ubiquitin-proteasome system dysfunction in the pathogenesis of spongiform neurodegeneration. The link between aberrant ubiquitination and spongiform neurodegeneration has been strengthened by the discovery that a null mutation in the E3 ubiquitin-protein ligase mahogunin ring finger-1 (Mgrn1) causes an autosomal recessively inherited form of spongiform neurodegeneration in animals. Recent studies have begun to suggest that abnormal ubiquitination may alter intracellular signaling and cell functions via proteasome-dependent and proteasome-independent mechanisms, leading to spongiform degeneration and neuronal cell death. Further elucidation of the pathogenic pathways involved in spongiform neurodegeneration should facilitate the development of novel rational therapies for treating prion diseases, HIV infection, and other spongiform degenerative disorders.
海绵状变性的特征是神经组织出现空泡化，并伴有神经元死亡和胶质细胞增生。尽管海绵状变性是朊病毒疾病的标志，但这种病理变化也存在于患有阿尔茨海默病、弥漫性路易体病、人类免疫缺陷病毒（HIV）感染和卡纳万海绵状脑白质营养不良的患者大脑中。这些不同疾病中海绵状变性的共同结果表明，共同的细胞机制必定是中枢神经系统中海绵状变化和神经变性过程的基础。对脑组织的免疫组织化学分析显示，在海绵状变化区域及其周围，泛素免疫反应性增强，这表明泛素 - 蛋白酶体系统功能障碍参与了海绵状神经变性的发病机制。E3泛素蛋白连接酶马霍古宁环指蛋白1（Mgrn1）的无效突变会导致动物出现常染色体隐性遗传形式的海绵状神经变性，这一发现进一步加强了异常泛素化与海绵状神经变性之间的联系。最近的研究开始表明，异常泛素化可能通过蛋白酶体依赖性和蛋白酶体非依赖性机制改变细胞内信号传导和细胞功能，导致海绵状变性和神经元细胞死亡。进一步阐明海绵状神经变性所涉及的致病途径，应有助于开发出治疗朊病毒疾病、HIV感染及其他海绵状变性疾病的新型合理疗法。
