The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea
The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea
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DOI：
10.1093/brain/awl332
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发表时间：
2007-01-01
期刊：
影响因子：
14.5
通讯作者：
Parent, Andre
中科院分区：
文献类型：
--
作者：
Huot, Philippe;Levesque, Martin;Parent, Andre
纹状体含有一群多巴胺能神经元，被认为是多巴胺（DA）的局部来源。这种神经元群体在帕金森病的动物模型中的大小增加，其中纹状体DA水平低，但其在特发性帕金森病和亨廷顿舞蹈病中的命运知之甚少。在这项研究中，我们使用的抗体对酶酪氨酸羟化酶（TH），多巴胺能神经元的一个忠实的标志物，比较，通过体视学计数方法，纹状体TH+神经元的数量从帕金森氏病患者，亨廷顿氏病患者和年龄匹配的控制尸检脑切片。还进行碘化丙啶核染色，以避免计数短TH+轴突段，其具有大的肿胀静脉曲张，类似于小的双极神经元。在正常受试者中，TH+神经元分散在整个纹状体，但他们丰富的优先在腹侧部分的结构和更多的壳核比在尾状核。它们显示出中等大小的多极细胞体（直径10-20 μ m），发出3-5个光滑树突，这是纹状体中间神经元的典型特征。这些TH+细胞很少被发现在小TH-穷人的纹状体，他们中的大多数被嵌入在大TH-丰富的extrriosomal矩阵。纹状体TH+神经元的数量也被发现根据与受试者的年龄成反比关系而变化。在病理大脑中，纹状体TH+神经元的形态特征相对不变，但这种神经元的数量显着减少与对照组相比。帕金森病患者的纹状体中TH+神经元的数量比对照组少六倍，而亨廷顿病患者的纹状体中基本上没有这种神经元。这些发现与帕金森病的啮齿动物和猴子模型中获得的结果不一致，据报道，其中纹状体TH+神经元的数量在DA去神经支配后显着增加。由于在本研究中检查的帕金森病患者都用l-3，4-二羟基苯丙氨酸治疗以补偿纹状体DA的损失，并且据报道与对照相比，亨廷顿病患者的纹状体中纹状体DA的水平更高，因此我们假设局部DA浓度对纹状体中间神经元的TH表型表达产生负反馈。更好地了解这种异位神经元群体的体内状态的控制因素可以为帕金森病和亨廷顿舞蹈病的治疗开辟新的治疗途径。
The striatum harbours a population of dopaminergic neurons that is thought to act as a local source of dopamine (DA). This neuronal population increases in size in animal models of Parkinson's disease, where striatal DA levels are low, but its fate in idiopathic Parkinson's disease and Huntington's chorea is poorly known. In this study, we used antibodies raised against the enzyme tyrosine hydroxylase (TH), a faithful marker of dopaminergic neurons, to compare, by means of stereological counting methods, the number of striatal TH+ neurons on post-mortem brain sections from Parkinson's disease patients, Huntington's disease patients and age-matched controls. Propidium iodide nuclear staining was also performed to avoid counting short TH+ axonal segments that bear a large swollen varicosity and resemble small bipolar neurons. In normal subjects, TH+ neurons were scattered throughout the striatum, but they abounded preferentially in the ventral portion of the structure and were more numerous in the putamen than in the caudate nucleus. They displayed a multipolar cell body of medium size (10-20 mu m in diameter) that emitted 3-5 smooth dendrites, a typical characteristic of striatal interneurons. These TH+ cells were rarely found in the small TH-poor striosomes, most of them being embedded in the large TH-rich extrastriosomal matrix. The number of striatal TH+ neurons was also found to vary according to an inverse relation with the age of the subjects. In pathological brains, the morphological characteristics of the striatal TH+ neurons were relatively unaltered, but the number of such neurons was markedly reduced compared with controls. The striatum of Parkinson's disease patients was found to contain six times less TH+ neurons than that of controls, whereas the striatum of Huntington's disease patients was largely devoid of such neurons. These findings are at odds with the results obtained in rodent and monkey models of Parkinson's disease, in which the number of striatal TH+ neurons is reported to increase markedly following DA denervation. Since Parkinson's disease patients examined in this study were all treated with l-3,4-dihydroxyphenylalanine to compensate for the loss of striatal DA and that levels of striatal DA are reportedly higher in the striatum of Huntington's disease patients compared with controls, we hypothesize that local DA concentrations exert a negative feedback on the expression of TH phenotype by striatal interneurons. A better knowledge of factors governing the in vivo state of this ectopic neuronal population could open new therapeutic avenues for the treatment of Parkinson's disease and Huntington's chorea.