Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning
Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning
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DOI：
10.1093/hmg/ddr573
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发表时间：
2012-03-15
影响因子：
3.5
通讯作者：
Guo, Ming
中科院分区：
文献类型：
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作者：
Dodson, Mark W.;Zhang, Ting;Guo, Ming
LRRK2（PARK8）是帕金森病（PD）最常见的遗传决定因素，LRRK2中的显性突变导致遗传性PD，LRRK2基因座的序列变异与散发性PD的风险增加相关。尽管LRRK2已经涉及几乎所有细胞区室的多种细胞过程，但LRRK2的确切功能仍不清楚。在这里，我们表明，果蝇同源LRRK2（Lrrk）定位于膜的晚期内体和溶酶体，物理相互作用的晚期内体运输Rab7的关键介质和负调节Rab7依赖的核周定位的溶酶体。我们还表明，类似于致病性LRRK2（G2019S）等位基因的突变形式的lrrk的行为相反，野生型lrrk，它促进而不是抑制rab7依赖的核周溶酶体集群，与这些影响的突变lrrk的溶酶体位置需要微管和动力蛋白。这些数据表明，LRRK2通常在Rab7依赖性溶酶体定位中起作用，并且该功能被最常见的PD引起的LRRK2突变破坏，将内溶酶体功能障碍与LRRK2介导的PD的发病机制联系起来。
LRRK2 (PARK8) is the most common genetic determinant of Parkinsons disease (PD), with dominant mutations in LRRK2 causing inherited PD and sequence variation at the LRRK2 locus associated with increased risk for sporadic PD. Although LRRK2 has been implicated in diverse cellular processes encompassing almost all cellular compartments, the precise functions of LRRK2 remain unclear. Here, we show that the Drosophila homolog of LRRK2 (Lrrk) localizes to the membranes of late endosomes and lysosomes, physically interacts with the crucial mediator of late endosomal transport Rab7 and negatively regulates rab7-dependent perinuclear localization of lysosomes. We also show that a mutant form of lrrk analogous to the pathogenic LRRK2(G2019S) allele behaves oppositely to wild-type lrrk in that it promotes rather than inhibits rab7-dependent perinuclear lysosome clustering, with these effects of mutant lrrk on lysosome position requiring both microtubules and dynein. These data suggest that LRRK2 normally functions in Rab7-dependent lysosomal positioning, and that this function is disrupted by the most common PD-causing LRRK2 mutation, linking endolysosomal dysfunction to the pathogenesis of LRRK2-mediated PD.