The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration.
The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration.
复制标题
果蝇 hep 通路介导 Lrrk2 诱导的神经变性。
DOI：
10.1139/bcb-2017-0262
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Smith,WanliW
中科院分区：
文献类型：
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作者：
Yang,Dejun;Thomas,JosephM;Li,Tianxia;Lee,Youngseok;Liu,Zhaohui;Smith,WanliW
尽管帕金森病（PD）的发病机制尚不清楚，但富含亮氨酸重复序列激酶2（Lrrk 2）突变是家族性PD的主要病因之一。这些突变中的大多数破坏Lrrk 2激酶和（或）GT3结构域功能，导致神经元变性。然而，Lrrk 2诱导的神经元变性的信号通路尚未完全了解。越来越多的证据表明Lrrk 2的功能与MAP激酶（MAPK）级联反应之间存在联系。为了在体内进一步研究这种联系，在果蝇模型中进行MAPK通路的遗传RNAi筛选，以鉴定可以抑制G2019 S-Lrrk 2诱导的PD样表型的遗传修饰剂。结果显示，敲低半翅型（hep或JNKK）基因增加了果蝇的存活时间，改善了运动功能，并减少了G2019 S-Lrrk 2转基因果蝇中多巴胺能神经元的损失。JNK（JNK-DN）是一种位于hepin G2019 S-Lrrk 2转基因果蝇下游的激酶，其显性负性等位基因的表达引起了类似的效果。此外，用JNK抑制剂SP 600125处理部分逆转了G2019 S-Lrrk 2诱导的多巴胺能神经元损失。这些结果表明hepp 3通路在果蝇Lrrk 2连锁帕金森综合征中起重要作用。这些研究为Lrrk 2相关PD发病机制的分子机制提供了新的见解，并有助于确定潜在的治疗靶点。
Although the pathogenesis of Parkinson’s disease (PD) remains unclear, mutations inleucine-rich repeat kinase 2(Lrrk2) are among the major causes of familial PD. Most of these mutations disrupt Lrrk2 kinase and (or) GTPase domain function, resulting in neuronal degeneration. However, the signal pathways underlying Lrrk2-induced neuronal degeneration are not fully understood. There is an expanding body of evidence that suggests a link between Lrrk2 function andMAP kinase(MAPK) cascades. To further investigate this link in vivo, genetic RNAi screens of the MAPK pathways were performed in aDrosophilamodel to identify genetic modifier(s) that can suppress G2019S-Lrrk2-induced PD-like phenotypes. The results revealed that the knockdown ofhemipterous (hep, or JNKK) increased fly survival time, improved locomotor function, and reduced loss of dopaminergic neurons in G2019S-Lrrk2 transgenic flies. Expression of the dominant-negative allele of JNK (JNK-DN), a kinase that is downstream ofhepin G2019S-Lrrk2 transgenic flies, elicited a similar effect. Moreover, treatment with the JNK inhibitor SP600125 partially reversed the G2019S-Lrrk2-induced loss of dopaminergic neurons. These results indicate that theheppathway plays an important role in Lrrk2-linked Parkinsonism in flies. These studies provide new insights into the molecular mechanisms underlying Lrrk2-linked PD pathogenesis and aid in identifying potential therapeutic targets.