LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.
LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.
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DOI：
10.1038/nn.3636
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发表时间：
2014-03
影响因子：
25
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
--
作者：
Parisiadou, Loukia;Yu, Jia;Sgobio, Carmelo;Xie, Chengsong;Liu, Guoxiang;Sun, Lixin;Gu, Xing-Long;Lin, Xian;Crowley, Nicole A.;Lovinger, David M.;Cai, Huaibin
富含亮氨酸重复序列激酶2（LRRK2）在纹状体投射神经元（SPN）中富集。在这里，我们表明，LRRK2负调节蛋白激酶A（PKA）的活性在突触形成和响应多巴胺受体Drd1激活的SPN。LRRK2与PKA调节亚基II β（PKARII β）相互作用。LRRK2的缺乏促进PKA的突触易位，增加PKA介导的肌动蛋白分解酶cofilin和谷氨酸受体GluR1的磷酸化，导致发育中的SPN中异常的突触发生和传递。此外，PKA依赖性磷酸化的GluR1也异常增强的年轻和老年LRRK2-null小鼠的纹状体后，与Drd1激动剂治疗。值得注意的是，帕金森病相关的LRRK2 R1441C错义突变损害了LRRK2与PKARII β的相互作用，也诱导了SPN中过度的PKA活性。我们的研究结果揭示了LRRK2在PKA信号转导中的新的调节作用，并提供了帕金森病SPN功能障碍的新的致病机制。
Leucine-rich repeat kinase 2 (LRRK2) is enriched in the striatal projection neurons (SPNs). Here we show that LRRK2 negatively regulates protein kinase A (PKA) activity in the SPNs during synaptogenesis and in response to dopamine receptor Drd1 activation. LRRK2 interacted with PKA regulatory subunit IIβ (PKARIIβ). A lack of LRRK2 promoted the synaptic translocation of PKA and increased PKA-mediated phosphorylation of actin-disassembling enzyme cofilin and glutamate receptor GluR1, resulting in abnormal synaptogenesis and transmission in the developing SPNs. Furthermore, PKA-dependent phosphorylation of GluR1 was also aberrantly enhanced in the striatum of young and aged LRRK2-null mice after treatment with a Drd1 agonist. Notably, a Parkinson’s disease-related LRRK2 R1441C missense mutation that impaired the interaction of LRRK2 with PKARIIβ also induced excessive PKA activity in the SPNs. Our findings reveal a new regulatory role of LRRK2 in PKA signaling, and provide a new pathogenic mechanism of SPN dysfunction in Parkinson’s disease.
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影响因子：
25
作者：
Li, Yanping;Liu, Wencheng;Oo, Tinmarla F.;Wang, Lei;Tang, Yi;Jackson-Lewis, Vernice;Zhou, Chun;Geghman, Kindiya;Bogdanov, Mikhail;Przedborski, Serge;Beal, M. Flint;Burke, Robert E.;Li, Chenjian
通讯作者：
Li, Chenjian
影响因子：
16
作者：
Andrianantoandro, Ernesto;Pollard, Thomas D.
通讯作者：
Pollard, Thomas D.
影响因子：
6.1
作者：
Chandran, Jayanth S.;Lin, Xian;Cai, Huaibin
通讯作者：
Cai, Huaibin
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
作者：
GLASER, EM;VANDERLOOS, H
通讯作者：
VANDERLOOS, H