Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: Human midbrain dopamine neurons
Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: Human midbrain dopamine neurons
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DOI：
10.1002/cne.20098
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发表时间：
2004-05-17
影响因子：
2.5
通讯作者：
German, DC
中科院分区：
文献类型：
--
作者：
Liang, CL;Nelson, O;German, DC
在帕金森病（PD）中，腹侧黑质（SN）中的多巴胺能神经元比腹侧被盖区（VTA）中的多巴胺能神经元更容易变性。腹侧黑质神经元也比腹侧被盖区的多巴胺能神经元含有更多的神经黑色素。体外数据表明，神经黑色素是由过量的胞质儿茶酚胺形成的，其不通过囊泡单胺转运蛋白-2（VMAT 2）积累到突触囊泡中。通过使用定量免疫组织化学方法在人死后的大脑，我们试图检查VMAT 2的相对含量的神经元内含有不同量的神经黑色素。测定VMAT 2和多巴胺合成限速酶酪氨酸羟化酶（TH）的免疫染色强度（ISI）。ISI测量取自腹侧SN区域，其中神经元最容易在PD中变性，黑体-1（NI）;取自腹侧SN区域，其中细胞中度容易在PD中变性，基质（M）;以及取自靠近第三神经出口的VTA神经元（亚区111）。数据表明：1）与NI神经元相比，III亚区神经元具有显著更高的VMAT 2 ISI水平（2）在NI和III神经元中，VMAT 2 ISI与神经黑色素呈负相关;（3）在N1、M和III亚区中，VMAT 2 ISI与PD的变性易感性呈负相关; 4）VMAT 2 ISI高的神经元也有TH ISI高。这些数据支持这一假设，即中脑多巴胺能神经元，合成更大量的多巴胺有更多的囊泡存储容量的动作电位诱导释放的递质和腹侧SN神经元积累最神经黑色素，部分是因为他们有最少的VMAT 2蛋白。(C)2004 Wiley-Liss，Inc.
The dopaminergic neurons in the ventral substantia nigra (SN) are significantly more vulnerable to degeneration in Parkinson's disease (PD) than the dopaminergic neurons in the ventral tegmental area (VTA). The ventral SN neurons also contain significantly more neuromelanin pigment than the dopaminergic neurons in the VTA. In vitro data indicate that neuromelanin pigment is formed from the excess cytosolic catecholamine that is not accumulated into synaptic vesicles by the vesicular monoamine transporter-2 (VMAT2). By using quantitative immunohistochemical methods in human postmortem brain, we sought to examine the relative contents of VMAT2 within neurons that contain different amounts of neuromelanin pigment. The immunostaining intensity (ISI) was measured for VMAT2 and also for the rate-limiting enzyme for the synthesis of dopamine, tyrosine hydroxylase (TH). ISI measures were taken from the ventral SN region where neurons are most vulnerable to degeneration in PD, nigrosome-1 (NI); from the ventral SN region where cells are moderately vulnerable to degeneration in PD, the matrix (M); and from VTA neurons near the exit of the third nerve (subregion 111). The data indicate that 1) subregion III neurons have significantly higher levels of VMAT2 ISI compared with NI neurons (more than twofold) and M neurons (45%); 2) there is an inverse relationship between VMAT2 ISI and neuromelanin pigment in the NI and III neurons; 3) there is an inverse relationship between VMAT2 ISI and the vulnerability to degeneration in PD in the N1, M, and III subregions; and 4) neurons with high VMAT2 ISI also have high TH ISI. These data support the hypothesis that midbrain dopaminergic neurons that synthesize greater amounts of dopamine have more vesicular storage capacity for action potential-induced release of transmitter and that the ventral SN neurons accumulate the most neuromelanin pigment, in part because they have the least VMAT2 protein. (C) 2004 Wiley-Liss, Inc.