Mutant α-synuclein-induced degeneration is reduced by parkin in a fly model of Parkinson's disease
Mutant α-synuclein-induced degeneration is reduced by parkin in a fly model of Parkinson's disease
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DOI：
10.1139/g06-011
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发表时间：
2006-05-01
期刊：
影响因子：
3.1
通讯作者：
Staveley, Brian E.
中科院分区：
文献类型：
--
作者：
Haywood, Annika F. M.;Staveley, Brian E.
帕金森病（PD）患者表现出由多巴胺能神经元变性引起的特征性运动控制丧失。编码α-突触核蛋白和帕金蛋白的基因突变与这种疾病的遗传形式有关。帕金蛋白作为泛素连接酶发挥作用，靶向蛋白质进行降解。人α-突触核蛋白亚型在果蝇神经系统中的表达形成了一个极好的遗传模型的基础，该模型概括了PD的表型和行为特征。使用这个模型，我们分析了parkin共表达对衰老果蝇的攀爬能力、寿命和视网膜变性的影响。我们已经确定parkin的共表达可以抑制由突变体α-突触核蛋白的表达引起的表型。在发育中的眼睛中，帕金可以减少视网膜变性。当在多巴胺能神经元中共表达时，攀爬的能力随着时间的推移而延长。如果在人类中是保守的，我们认为帕金蛋白的上调可能证明是抑制突变形式的α-突触核蛋白诱导的PD的方法。
Parkinson's disease (PD) patients show a characteristic loss of motor control caused by the degeneration of dopaminergic neurons. Mutations in the genes that encode alpha-synuclein and parkin have been linked to inherited forms of this disease. The parkin protein functions as a ubiquitin ligase that targets proteins for degradation. Expression of isoforms of human alpha-synuclein in the Drosophila melanogaster nervous system forms the basis of an excellent genetic model that recapitulates phenotypic and behavioural features of PD. Using this model, we analysed the effect of parkin co-expression on the climbing ability of aging flies, their life span, and their retinal degeneration. We have determined that co-expression of parkin can suppress phenotypes caused by expression of mutant alpha-synuclein. In the developing eye, parkin reduces retinal degeneration. When co-expressed in the dopaminergic neurons, the ability to climb is extended over time. If conserved in humans, we suggest that upregulation of parkin may prove a method of suppression for PD induced by mutant forms of alpha-synuclein.