Wlds-Mediated Protection of Dopaminergic Fibers in an Animal Model of Parkinson Disease
Wlds-Mediated Protection of Dopaminergic Fibers in an Animal Model of Parkinson Disease
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DOI：
10.1016/j.cub.2004.01.053
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发表时间：
2004-02
期刊：
影响因子：
9.2
通讯作者：
A. Sajadi;B. Schneider;P. Aebischer
中科院分区：
文献类型：
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作者：
A. Sajadi;B. Schneider;P. Aebischer
帕金森病（Parkinson disease，PD）是一种以黑质多巴胺能神经元向纹状体的进行性变性为特征的疾病。由于纹状体多巴胺的不足是PD症状的主要原因，因此保留轴突终末似乎至关重要[1]。在Wldsmice [2-5]中观察到显著的轴突保护免受周围神经沃勒变性，这是一种由自发显性突变[6]赋予的表型。为了评估PD模型中任何Wlds介导的多巴胺纤维拯救，用6-羟基多巴胺（6-OHDA）（一种儿茶酚胺能神经毒素）损伤Wldsmice的黑质纹状体通路[7]。在内侧前脑束中注射6-OHDA后，Wldsmice在纹状体中显示出显著的多巴胺纤维保护作用。药物诱导的旋转行为证实了黑质纹状体纤维释放多巴胺的能力，虽然揭示了一个异常的神经递质控制可能是由于破坏轴突运输。在纹状体中部注射6-OHDA后，仅观察到保护趋势。值得注意的是，黑质纹状体损伤后，黑质多巴胺能细胞体没有受到保护。除了在亚细胞区室之间的变性过程中显示出细微的差异外，在PD动物模型中，Wlds介导的多巴胺轴突终末的保护可能会导致对轴突损失的机制的理解和新的治疗方法的开发。
Parkinson disease (PD) is characterized by the progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Since the deficit in striatal dopamine is the main cause of PD symptoms, it appears critical to preserve axon terminals [1]. Significant axon protection from peripheral nerve Wallerian degeneration is observed inWldsmice [2–5], a phenotype conferred by a spontaneous dominant mutation [6]. To assess anyWlds-mediated rescue of dopamine fibers in a PD model, the nigrostriatal pathway ofWldsmice was lesioned with 6-hydroxydopamine (6-OHDA), a catecholaminergic neurotoxin [7]. Following 6-OHDA injection in the medial forebrain bundle,Wldsmice showed remarkable dopamine fiber protection in the striatum. Drug-induced rotational behavior confirmed the nigrostriatal fiber ability to release dopamine, although revealing an abnormal neurotransmitter control presumably due to disrupted axonal transport. Following 6-OHDA injection in the midstriatum, only a protection trend was observed. Strikingly, no protection ofWldsnigral dopaminergic cell bodies was obtained following either nigrostriatal lesion. Besides showing subtle differences in the degeneration process between subcellular compartments, the reportedWlds-mediated protection of the dopamine axon terminals in an animal model of PD may lead to the understanding of mechanisms underlying axon loss and to the development of new therapeutic approaches.