Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.
Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.
复制标题
DOI：
10.1371/journal.pbio.3001480
复制
发表时间：
2021-12
期刊：
影响因子：
9.8
通讯作者：
Cookson MR
中科院分区：
文献类型：
--
作者：
Mamais A;Kluss JH;Bonet-Ponce L;Landeck N;Langston RG;Smith N;Beilina A;Kaganovich A;Ghosh MC;Pellegrini L;Kumaran R;Papazoglou I;Heaton GR;Bandopadhyay R;Maio N;Kim C;LaVoie MJ;Gershlick DC;Cookson MR
富亮氨酸重复激酶2 （LRRK2）突变导致常染色体显性帕金森病（PD），而多态LRRK2变异与散发性PD相关。pd相关突变增加LRRK2激酶活性，诱导体外和体内神经毒性。小GTPase Rab8a是LRRK2激酶的底物，参与受体介导的再循环和转铁蛋白的内吞运输，但pd相关的LRRK2突变对Rab8a功能的影响尚不清楚。在这里，我们发现在过表达细胞模型中，LRRK2的功能获得突变诱导内源性Rab8a被隔离到溶酶体上，而LRRK2激酶活性的药物抑制逆转了这种表型。此外，我们发现LRRK2突变驱动内吞转铁蛋白与rab8a阳性溶酶体的关联。LRRK2已被认为是促炎信号下游细胞反应的一个组成部分，并在死后PD组织的小胶质细胞中被激活。在这里，我们发现ipsc衍生的小胶质细胞携带最常见的LRRK2突变G2019S，在促炎条件下将转铁蛋白误转运到核近端溶酶体。此外，与野生型小鼠相比，G2019S敲入小鼠在纹状体内注射LPS后，小胶质细胞中的铁沉积显著增加，并伴有纹状体铁蛋白的积累。我们的数据支持LRRK2在小胶质细胞促炎刺激下调节铁摄取和储存的作用。脑铁沉积是帕金森病的一个病理特征，但它是如何导致神经变性的尚不清楚。这项研究表明，LRRK2与帕金森病相关的突变导致体内异常的脑铁积累和体外铁平衡失调，支持LRRK2在小胶质细胞促炎刺激下调节铁摄取和储存的作用。
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia. Brain iron deposition is a feature of Parkinson’s disease pathology, but how this contributes to neurodegeneration is unclear. This study show that Parkinson’s disease-linked mutations in LRRK2 cause aberrant brain iron accumulation in vivo and iron dyshomeostasis in vitro, supporting a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.
登录
查看更多内容
影响因子：
2.9
作者：
Faucheux, BA;Hauw, JJ;Hirsch, EC
通讯作者：
Hirsch, EC
影响因子：
4
作者：
Hockey LN;Kilpatrick BS;Eden ER;Lin-Moshier Y;Brailoiu GC;Brailoiu E;Futter CE;Schapira AH;Marchant JS;Patel S
通讯作者：
Patel S
通过定量磁敏感图测量帕金森病中铁的区域渐进积累
影响因子：
2.9
作者：
Guan X;Xuan M;Gu Q;Huang P;Liu C;Wang N;Xu X;Luo W;Zhang M
通讯作者：
Zhang M
DOI：
10.15252/embj.2020104494
发表时间：
2020-09-15
期刊：
The EMBO journal
影响因子：
--
作者：
Herbst S;Campbell P;Harvey J;Bernard EM;Papayannopoulos V;Wood NW;Morris HR;Gutierrez MG
通讯作者：
Gutierrez MG
DOI：
10.1038/s41531-017-0010-8
发表时间：
2017
期刊：
NPJ Parkinson's disease
影响因子：
--
作者：
Cook DA;Kannarkat GT;Cintron AF;Butkovich LM;Fraser KB;Chang J;Grigoryan N;Factor SA;West AB;Boss JM;Tansey MG
通讯作者：
Tansey MG