The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human.
The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human.
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DOI：
10.1042/bcj20180248
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发表时间：
2018-06-06
期刊：
影响因子：
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通讯作者：
Alessi DR
中科院分区：
文献类型：
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作者：
Mir R;Tonelli F;Lis P;Macartney T;Polinski NK;Martinez TN;Chou MY;Howden AJM;König T;Hotzy C;Milenkovic I;Brücke T;Zimprich A;Sammler E;Alessi DR
LRRK2(富含亮氨酸的重复蛋白激酶-2)和VPS35基因的错义突变导致常染色体显性遗传帕金森病。VPS35基因编码逆转录复合体的货物结合成分，而LRRK2通过磷酸化Rab蛋白的亚群来调节囊泡运输。LRRK2的致病突变增加了它的激酶活性。目前尚不清楚到目前为止唯一被描述的致病VPS35突变[p.D620N]是如何发挥作用的。我们发现，在小鼠胚胎成纤维细胞中，VPS35[D620N]敲入突变显著提高了LRRK2介导的Rab8A、Rab10和Rab12的磷酸化。VPS35[D620N]突变还增加了小鼠组织(肺、肾、脾和脑)中Rab10的磷酸化。此外，与健康供者和特发性帕金森患者相比，LRRK2介导的Rab10磷酸化在3例VPS35[D620N]杂合突变的帕金森患者的中性粒细胞和单核细胞中增加。在野生型、LRRK2[R1441C]或VPS35[D620N]细胞中，VPS35的敲除或敲除显著抑制了LRRK2介导的Rab10的磷酸化。最后，VPS35[D620N]突变比LRRK2致病突变更能促进Rab10的磷酸化。现有数据表明，携带VPS35[D620N]的帕金森患者比携带LRRK2突变的患者患上这种疾病的年龄更早。我们的观察表明，VPS35控制LRRK2的活性，VPS35[D620N]突变导致功能获得，可能通过LRRK2激酶的过度激活而导致帕金森病。我们的发现表明，有可能精心设计针对逆转录复合体的化合物来抑制LRRK2的活性。此外，与VPS35[D620N]相关的帕金森氏症患者可能会从LRRK2抑制剂治疗中受益，该治疗已进入人体临床试验。
Missense mutations in the LRRK2 (Leucine-rich repeat protein kinase-2) and VPS35 genes result in autosomal dominant Parkinson's disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [p.D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation strikingly elevates LRRK2-mediated phosphorylation of Rab8A, Rab10, and Rab12 in mouse embryonic fibroblasts. The VPS35[D620N] mutation also increases Rab10 phosphorylation in mouse tissues (the lung, kidney, spleen, and brain). Furthermore, LRRK2-mediated Rab10 phosphorylation is increased in neutrophils as well as monocytes isolated from three Parkinson's patients with a heterozygous VPS35[D620N] mutation compared with healthy donors and idiopathic Parkinson's patients. LRRK2-mediated Rab10 phosphorylation is significantly suppressed by knock-out or knock-down of VPS35 in wild-type, LRRK2[R1441C], or VPS35[D620N] cells. Finally, VPS35[D620N] mutation promotes Rab10 phosphorylation more potently than LRRK2 pathogenic mutations. Available data suggest that Parkinson's patients with VPS35[D620N] develop the disease at a younger age than those with LRRK2 mutations. Our observations indicate that VPS35 controls LRRK2 activity and that the VPS35[D620N] mutation results in a gain of function, potentially causing PD through hyperactivation of the LRRK2 kinase. Our findings suggest that it may be possible to elaborate compounds that target the retromer complex to suppress LRRK2 activity. Moreover, patients with VPS35[D620N] associated Parkinson's might benefit from LRRK2 inhibitor treatment that have entered clinical trials in humans.