Kozina Elena A, Khakimova Gulnara R, Khaindrava Vitaly G, Kucheryanu Valeriayn G, Vorobyeva Nadezhda E, Krasnov Alexey N, Georgieva Sophia G, Kerkerian-Le Goff Lidiya, Ugrumov Michael V
Laboratory of Hormonal Regulations, Institute of Developmental Biology RAS, Moscow, Russia; Laboratory of Neurohistology, Institute of Normal Physiology RAMS, Moscow, Russia.
Laboratory of Neurohistology, Institute of Normal Physiology RAMS, Moscow, Russia; IC2N, IBDML, UMR6216 CNRS-Université de la Méditerranée, Marseille, France.
J Neurol Sci. 2014 May 15;340(1-2):198-207. doi: 10.1016/j.jns.2014.03.028. Epub 2014 Mar 21.
Progressive degeneration of nigrostriatal dopaminergic (DA-ergic) neurons is a key component in the pathogenesis of Parkinson's disease, which develops for a long time at the preclinical stage with no motor dysfunctions due to the initiation of compensatory processes. The goal of this study was to evaluate the changes in surviving nigrostriatal DA-ergic neurons with focus on tyrosine hydroxylase (TH) in MPTP-treated mice at the presymptomatic and early symptomatic stages of parkinsonism. According to our data, a partial degeneration of DA-ergic neurons at the presymptomatic stage was accompanied by: (i) no change in TH mRNA content in the substantia nigra (SN) suggesting a compensatory increase of TH gene expression in individual neurons; (ii) a decrease of TH protein content in the nigrostriatal system and no change in individual neurons, suggesting a slowdown of TH translation. When comparing DA-ergic neurons at the early symptomatic stage and presymptomatic stage, it becomes evident: (i) a decrease of TH mRNA content in the SN and hence gene expression in individual neurons; (ii) a decrease of TH content in the striatum and its increase in the SN and individual neurons suggesting an acceleration of TH translation. TH activity, an index of the rate of DA synthesis, was unchanged in the SN and decreased in the striatum to the same degree at both stages of parkinsonism. In the meantime, TH activity in individual neurons appeared to be compensatory increased, but to a higher degree at the symptomatic stage than at the presymptomatic one. These data first show that DA depletion, which provokes motor dysfunction, is not a result of the decrease of TH activity and the rate of DA synthesis but is rather related to either a decrease of DA release or an increase of DA uptake in striatal DA-ergic axons.
黑质纹状体多巴胺能（DA能）神经元的进行性变性是帕金森病发病机制的关键组成部分，该病在临床前期长时间发展，由于代偿过程的启动而无运动功能障碍。本研究的目的是评估在帕金森病无症状和早期症状阶段，经MPTP处理的小鼠中存活的黑质纹状体DA能神经元的变化，重点关注酪氨酸羟化酶（TH）。根据我们的数据，无症状阶段DA能神经元部分变性伴有：（i）黑质（SN）中TH mRNA含量无变化，提示单个神经元中TH基因表达代偿性增加；（ii）黑质纹状体系统中TH蛋白含量降低，单个神经元中无变化，提示TH翻译减慢。比较早期症状阶段和无症状阶段的DA能神经元时，明显可见：（i）SN中TH mRNA含量降低，因此单个神经元中基因表达降低；（ii）纹状体中TH含量降低，而SN和单个神经元中TH含量增加，提示TH翻译加速。TH活性是DA合成速率的指标，在帕金森病的两个阶段，SN中的TH活性均未改变，纹状体中的TH活性均同等程度降低。同时，单个神经元中的TH活性似乎代偿性增加，但在症状阶段比无症状阶段增加程度更高。这些数据首次表明，引发运动功能障碍的DA耗竭不是TH活性降低和DA合成速率降低的结果，而是与纹状体DA能轴突中DA释放减少或DA摄取增加有关。
