Loss of PINK1 function affects development and results in neurodegeneration in zebrafish
Loss of PINK1 function affects development and results in neurodegeneration in zebrafish
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DOI：
10.1523/jneurosci.0979-08.2008
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发表时间：
2008-08-13
影响因子：
5.3
通讯作者：
Rubinsztein, David C.
中科院分区：
文献类型：
--
作者：
Anichtchik, Oleg;Diekmann, Heike;Rubinsztein, David C.
帕金森病（PD）是西方世界第二大流行的神经退行性疾病。PTEN（10号染色体上的磷酸酶/张力蛋白同源物）诱导的推定激酶1（PINK 1），一种在常染色体隐性形式的PD中突变的推定激酶，也与该疾病的散发病例有关。虽然突变似乎导致功能丧失，但这种蛋白质的作用以及PINK 1 PD中涉及的途径仍知之甚少。在这里，我们产生了一个脊椎动物模型的PINK 1不足，使用吗啉寡核苷酸敲低斑马鱼（Danio rerio）。PINK 1敲低导致严重的发育表型，其由野生型人PINK 1 mRNA拯救。变形体表现出中枢多巴胺能神经元数量的中度减少和线粒体功能的改变，包括半胱天冬酶-3活性和活性氧簇（ROS）水平的增加。当吗啡类药物暴露于几种具有抗氧化特性的药物时，ROS水平正常化，相关表型得到改善。此外，GSK 3 β相关机制可以解释PINK 1敲低的一些效应，因为变形鱼显示出升高的GSK 3 β活性，并且它们的表型被GSK 3 β抑制剂如LiCl和SB 216763 [3-（2，4-二氯苯基）-4-（1-甲基-1H-吲哚-3-基）1H-吡咯-2，5-二酮]部分消除。这为PINK 1的生物学提供了新的见解，并为进一步研究提供了可能的治疗途径。
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the Western world. PTEN (phosphatase/tensin homolog on chromosome 10)-induced putative kinase 1 (PINK1), a putative kinase that is mutated in autosomal recessive forms of PD, is also implicated in sporadic cases of the disease. Although the mutations appear to result in a loss of function, the roles of this protein and the pathways involved in PINK1 PD are poorly understood. Here, we generated a vertebrate model of PINK1 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio). PINK1 knockdown results in a severe developmental phenotype that is rescued by wild-type human PINK1 mRNA. Morphants display a moderate decrease in the numbers of central dopaminergic neurons and alterations of mitochondrial function, including increases in caspase-3 activity and reactive oxygen species (ROS) levels. When the morphants were exposed to several drugs with antioxidant properties, ROS levels were normalized and the associated phenotype improved. In addition, GSK3 beta-related mechanisms can account for some of the effects of PINK1 knockdown, as morphant fish show elevated GSK3 beta activity and their phenotype is partially abrogated by GSK3 beta inhibitors, such as LiCl and SB216763 [3-(2,4dichlorophenyl)-4-(1-methyl-1H-indol-3-yl) 1H-pyrrole-2,5-dione]. This provides new insights into the biology of PINK1 and a possible therapeutic avenue for further investigation.