GTP-binding inhibitors increase LRRK2-linked ubiquitination and Lewy body-like inclusions.
GTP-binding inhibitors increase LRRK2-linked ubiquitination and Lewy body-like inclusions.
复制标题
GTP 结合抑制剂可增加 LRRK2 相关的泛素化和路易体样内含物。
DOI：
10.1002/jcp.29632
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发表时间：
2020
影响因子：
5.6
通讯作者：
Smith,WanliW
中科院分区：
文献类型：
--
作者：
Thomas,JosephM;Wang,Xiaobo;Guo,Gongbo;Li,Tianxia;Dai,Bingling;Nucifora,LeslieG;NuciforaJr,FrederickC;Liu,Zhaohui;Xue,Fengtian;Liu,Chunfeng;Ross,ChristopherA;Smith,WanliW
帕金森病（Parkinson's disease，PD）是一种最常见的运动障碍性疾病，主要表现为多巴胺能神经元的缺失和脑内路易体的出现。然而，目前尚不清楚路易体（包含蛋白质聚集）的形成如何发生。富含亮氨酸重复序列激酶2（LRRK 2）的突变可导致遗传形式的PD，并导致散发性PD伴典型路易体病理。在这里，我们使用我们最近发现的LRRK 2 GTP结合抑制剂作为药理学探针来研究LRRK 2连接的泛素化和蛋白质聚集。GTP结合抑制剂（68和Fx 2149）对GTP结合的药理学抑制主要通过K27连接增加LRRK 2连接的泛素化。化合物68-或Fx 2149增加了G2019 S-LRRK 2-连接的泛素化聚集体，其通过非典型连接类型K27和K63发生。K27 R和K63 R的共表达通过K27和K63连接阻止了泛素化，逆转了68和Fx 2149的作用。此外，68和Fx 2149还通过K27和K63连接促进G2019 S-LRRK 2连接的攻击体（Lewy小体样包涵体）形成。这些发现表明，LRRK 2 GTP结合活性在LRRK 2连接的泛素化和聚集形成中至关重要。这些研究为LRRK 2相关路易体样包涵体形成的PD发病机制提供了新的见解。
Parkinson's disease (PD) is one of the most common movement disorders with loss of dopaminergic neurons and the presence of Lewy bodies in certain brain areas. However, it is not clear how Lewy body (inclusion with protein aggregation) formation occurs. Mutations in leucine‐rich repeat kinase 2 (LRRK2) can cause a genetic form of PD and contribute to sporadic PD with the typical Lewy body pathology. Here, we used our recently identified LRRK2 GTP‐binding inhibitors as pharmacological probes to study the LRRK2‐linked ubiquitination and protein aggregation. Pharmacological inhibition of GTP‐binding by GTP‐binding inhibitors (68 and Fx2149) increased LRRK2‐linked ubiquitination predominantly via K27 linkage. Compound 68‐ or Fx2149 increased G2019S‐LRRK2‐linked ubiquitinated aggregates, which occurred through the atypical linkage types K27 and K63. Coexpression of K27R and K63R, which prevented ubiquitination via K27 and K63 linkages, reversed the effects of 68 and Fx2149. Moreover, 68 and Fx2149 also promoted G2019S‐LRRK2‐linked aggresome (Lewy body‐like inclusion) formation via K27 and K63 linkages. These findings demonstrate that LRRK2 GTP‐binding activity is critical in LRRK2‐linked ubiquitination and aggregation formation. These studies provide novel insight into the LRRK2‐linked Lewy body‐like inclusion formation underlying PD pathogenesis.