Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice.
Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice.
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DOI：
10.1093/hmg/ddy232
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发表时间：
2018-09-15
影响因子：
3.5
通讯作者：
Harvey K
中科院分区：
文献类型：
--
作者：
Pellegrini L;Hauser DN;Li Y;Mamais A;Beilina A;Kumaran R;Wetzel A;Nixon-Abell J;Heaton G;Rudenko I;Alkaslasi M;Ivanina N;Melrose HL;Cookson MR;Harvey K
富含亮氨酸重复序列激酶2（LRRK 2）的突变与家族性帕金森病（PD）分离，LRRK 2周围的遗传变异有助于散发性疾病的风险。尽管敲除（KO）Lrrk 2或将致病性突变敲入小鼠生殖系中不会导致PD表型，但已报告了Lrrk 2 KO小鼠肾脏中的几种缺陷。为了了解LRRK 2在体内的功能，我们使用了一种无偏的方法来确定哪些蛋白质途径在LRRK 2 KO肾脏中受到影响。我们提名的变化在细胞膜相关蛋白，溶酶体蛋白酶，蛋白质参与囊泡运输和蛋白质翻译的控制。在表达致病性G2019 S LRRK 2突变的小鼠中未观察到变化。使用培养的肾上皮细胞，我们复制了溶酶体蛋白酶的积累，并证明了阳离子非依赖性甘露糖-6-磷酸受体的亚细胞分布的变化。这些结果表明，LRRK 2的丢失导致蛋白质翻译和运输的协调反应，并反对G2019 S突变的显性负作用。
Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson’s disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout (KO) of Lrrk2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of Lrrk2 KO mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 KO kidneys. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutation. Using cultured epithelial kidney cells, we replicated the accumulation of lysosomal proteases and demonstrated changes in subcellular distribution of the cation-independent mannose-6-phosphate receptor. These results show that loss of LRRK2 leads to co-ordinated responses in protein translation and trafficking and argue against a dominant negative role for the G2019S mutation.
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影响因子：
15.1
作者：
Jeong GR;Jang EH;Bae JR;Jun S;Kang HC;Park CH;Shin JH;Yamamoto Y;Tanaka-Yamamoto K;Dawson VL;Dawson TM;Hur EM;Lee BD
通讯作者：
Lee BD
DOI：
10.1016/j.bbrc.2009.08.163
发表时间：
2009-11-20
影响因子：
3.1
作者：
Greggio, Elisa;Taymans, Jean-Marc;Zhen, Eugene Yuejun;Ryder, John;Vancraenenbroeck, Renee;Beilina, Alexandra;Sun, Peng;Deng, Junpeng;Jaffe, Howard;Baekelandt, Veerle;Merchant, Kalpana;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
DOI：
10.1073/pnas.1318306111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Beilina, Alexandria;Rudenko, Iakov N.;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
16.2
作者：
Lin, Xian;Parisiadou, Loukia;Gu, Xing-Long;Wang, Lizhen;Shim, Hoon;Sun, Lixin;Xie, Chengsong;Long, Cai-Xia;Yang, Wan-Jou;Ding, Jinhui;Chen, Zsu Zsu;Gallant, Paul E.;Tao-Cheng, Jung-Hwa;Rudow, Gay;Troncoso, Juan C.;Liu, Zhihua;Li, Zheng;Cai, Huaibin
通讯作者：
Cai, Huaibin
影响因子：
3.7
作者：
Kawakami F;Yabata T;Ohta E;Maekawa T;Shimada N;Suzuki M;Maruyama H;Ichikawa T;Obata F
通讯作者：
Obata F