Center for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, 30 Marie Curie, Ottawa, Ontario, Canada K1N6N5.
Eur J Neurosci. 2010 Feb;31(4):623-33. doi: 10.1111/j.1460-9568.2010.07091.x. Epub 2010 Feb 5.
Mutations in the human PTEN-induced kinase 1 (PINK1) gene are linked to recessive familial Parkinson's disease. Animal models of altered PINK1 function vary greatly in their phenotypic characteristics. Drosophila pink1 mutants exhibit mild dopaminergic neuron degeneration and locomotion defects. Such defects are not observed in mice with targeted null mutations in pink1, although these mice exhibit impaired dopamine release and synaptic plasticity. Here, we report that in zebrafish, morpholino-mediated knockdown of pink1 function did not cause large alterations in the number of dopaminergic neurons in the ventral diencephalon. However, the patterning of these neurons and their projections are perturbed. This is accompanied by locomotor dysfunction, notably impaired response to tactile stimuli and reduced swimming behaviour. All these defects can be rescued by expression of an exogenous pink1 that is not a target of the morpholinos used. These results indicate that normal PINK1 function during development is necessary for the proper positioning of populations of dopaminergic neurons and for the establishment of neuronal circuits in which they are implicated.
人类 PTEN 诱导激酶 1（PINK1）基因突变与隐性家族性帕金森病有关。改变 PINK1 功能的动物模型在表型特征上差异很大。果蝇 pink1 突变体表现出轻微的多巴胺能神经元变性和运动缺陷。在靶向敲除 pink1 的小鼠中没有观察到这种缺陷，尽管这些小鼠表现出多巴胺释放和突触可塑性受损。在这里，我们报告在斑马鱼中，用 morpholino 介导的 pink1 功能敲低不会导致腹侧间脑多巴胺能神经元数量的大量改变。然而，这些神经元及其投射的模式被打乱。这伴随着运动功能障碍，特别是对触觉刺激的反应受损和游泳行为减少。所有这些缺陷都可以通过表达一种不是 morpholinos 靶标的外源性 pink1 来挽救。这些结果表明，在发育过程中正常的 PINK1 功能对于多巴胺能神经元群体的正确定位以及它们所涉及的神经元回路的建立是必要的。
