Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion:: Is this the target for Parkinson's disease?
Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion:: Is this the target for Parkinson's disease?
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DOI：
10.1016/j.nbd.2006.08.021
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发表时间：
2007-01-01
影响因子：
6.1
通讯作者：
Kordower, Jeffrey H.
中科院分区：
文献类型：
--
作者：
Chu, Yaping;Kordower, Jeffrey H.
α-突触核蛋白是一种突触蛋白，与帕金森病的病因和发病机制直接相关。我们以前已经表明，只有黑质神经元在PD表达α-突触核蛋白夹杂物显示损失多巴胺能表型。本研究验证了正常衰老有助于这种效应的假设。在18名18至102岁的正常人和24名2至34岁的恒河猴中，对单个黑质神经元内α-突触核蛋白的相对丰度进行了定量。光密度分析显示，在这两个物种的单个黑质神经元内α-突触核蛋白蛋白的一个强大的年龄相关的增加。这种效应对黑质α-突触核蛋白是特异性的，因为在腹侧被盖区没有发现年龄相关的变化，在黑质中也没有发现非致病性P-突触核蛋白的变化。黑质α-突触核蛋白的年龄相关性增加是非聚集的，与年龄相关的酪氨酸羟化酶（TH），多巴胺生产的限速酶的减少密切相关。事实上，只有表达α-突触核蛋白的细胞显示TH减少。我们假设，年龄相关的α-突触核蛋白的增加导致黑质纹状体多巴胺的阈下变性，在PD中，由于溶酶体功能障碍导致蛋白质错误折叠和包涵体形成而出现症状。我们进一步假设，预防非聚集α-突触核蛋白的年龄相关性积累可能是PD患者的一个简单而有效的治疗靶点。(c)2006年爱思唯尔公司All rights reserved.
alpha-Synuclein is a synaptic protein that has been directly linked to both the etiology and pathogenesis of Parkinson's disease. We have previously shown that only nigral neurons in PD expressing alpha-synuclein inclusions display a loss dopaminergic phenotype. The present study tested the hypothesis that normal aging contributes to this effect. The relative abundance of alpha-synuclein protein within individual nigral neurons was quantified in eighteen normal humans between the age of 18 and 102 and twenty four rhesus monkeys between the age of 2 and 34. Optical densitometry revealed a robust age-related increase in alpha-synuclein protein within individual nigral neurons in both species. This effect was specific for nigral alpha-synuclein as no age-related changes were found in the ventral tegmental area nor were there changes in the nigra for non-pathogenic P-synuclein. The age-related increases in nigral alpha-synuclein were non-aggregated and strongly associated with age-related decreases in tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine production. In fact, only cells expressing alpha-synuclein displayed reductions in TH. We hypothesize that age-related increases in alpha-synuclein result in a subthreshold degeneration of nigrostriatal dopamine which, in PD, becomes symptomatic due to lysosomal failure resulting in protein misfolding and inclusion formation. We further hypothesize that preventing the age-related accumulation of non-aggregated alpha-synuclein might be a simple and potent therapeutic target for patients with PD. (c) 2006 Elsevier Inc. All rights reserved.