Hashimoto Makoto, Rockenstein Edward, Masliah Eliezer
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
Ann N Y Acad Sci. 2003 Jun;991:171-88.
Accumulation and toxic conversion to protofibrils of alpha-synuclein has been associated with neurological disorders such as Parkinson's disease (PD), Lewy body disease, multiple system atrophy, neurodegeneration with brain iron accumulation type 1, and Alzheimer's disease. In recent years, modeling these disorders in transgenic (tg) mice and flies has helped improve understanding of the pathogenesis of these diseases and has established the basis for the development of new experimental treatments. Overexpression of alpha-synuclein in tg mice in a region- and cell-specific manner results in degeneration of selective circuitries accompanied by motor deficits and inclusion formation similar to what is found in PD and related disorders. Furthermore, studies in singly and doubly tg mice have shown that toxic conversion and accumulation can be accelerated by alpha-synuclein mutations associated with familial parkinsonism, by amyloid beta peptide 1-42 (Abeta 1-42), and by oxidative stress. In contrast, molecular chaperones such as Hsp70 and close homologues such as alpha-synuclein have been shown to suppress toxicity. Similar studies are underway to evaluate the effects of other modifying genes that might play a role in alpha-synuclein ubiquitination. Among them considerable interest has been placed on the role of molecules associated with familial parkinsonism (Parkin, UCHL-1). Furthermore, studying the targeted overexpression of alpha-synuclein and other modifier genes in the nigrostriatal and limbic system by using regulatable promoters, lentiviral vectors, and siRNA will help improve understanding of the molecular mechanisms involved in selective neuronal vulnerability, and it will aid the development of new treatments.
α-突触核蛋白的积累及其向原纤维的毒性转化与帕金森病(PD)、路易体病、多系统萎缩、1型脑铁沉积神经变性和阿尔茨海默病等神经系统疾病有关。近年来,在转基因(tg)小鼠和果蝇中对这些疾病进行建模有助于增进对这些疾病发病机制的理解,并为开发新的实验性治疗方法奠定了基础。以区域和细胞特异性方式在tg小鼠中过表达α-突触核蛋白会导致选择性神经回路退化,伴有运动缺陷和包涵体形成,类似于在PD及相关疾病中所见。此外,对单基因和双基因tg小鼠的研究表明,与家族性帕金森病相关的α-突触核蛋白突变、淀粉样β肽1-42(Aβ1-42)和氧化应激可加速毒性转化和积累。相反,分子伴侣如热休克蛋白70(Hsp70)以及α-突触核蛋白等密切同源物已被证明可抑制毒性。目前正在进行类似研究,以评估其他可能在α-突触核蛋白泛素化中起作用的修饰基因的影响。其中,与家族性帕金森病相关的分子(Parkin、泛素羧基末端水解酶L1,UCHL-1)的作用备受关注。此外,通过使用可调控启动子、慢病毒载体和小干扰RNA(siRNA)研究α-突触核蛋白和其他修饰基因在黑质纹状体和边缘系统中的靶向过表达,将有助于增进对选择性神经元易损性所涉及分子机制的理解,并有助于开发新的治疗方法。