Short- and long-term effects of LRRK2 on axon and dendrite growth.
Short- and long-term effects of LRRK2 on axon and dendrite growth.
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DOI：
10.1371/journal.pone.0061986
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Benson DL
中科院分区：
文献类型：
--
作者：
Sepulveda B;Mesias R;Li X;Yue Z;Benson DL
富亮氨酸重复激酶2 （LRRK2）突变是常染色体显性帕金森病（PD）的基础，在临床上与特发性PD难以区分。LRRK2的功能尚不清楚，但已被广泛接受的是，LRRK2水平或其激酶活性（通过最常见的突变（G2019S）增加）调节神经突生长。然而，增长并没有被衡量；目前尚不清楚平均长度差异是否对应于生长或收缩速率的改变，轴突或树突是否受到不同的影响，所观察到的影响是短暂的还是持续的。为了解决这些问题，我们比较了表达细菌人工染色体转基因小鼠培养的神经元的几个发育里程碑，这些转基因小鼠编码小鼠野生型Lrrk2或突变型Lrrk2 - g2019s、Lrrk2敲除小鼠和非转基因小鼠。在三周的层粘连蛋白发育过程中，数据显示Lrrk2 - g2019s对树突生长和树突化有持续的负面影响，但与预期相反，Lrrk2敲除小鼠的树突并没有更快地发育。相比之下，在生长较慢的底物聚l -赖氨酸上培养的年轻神经元，Lrrk2转基因神经元的轴突和树突运动性显著降低，Lrrk2敲除神经元的运动性显著增加，但长度没有显著变化。我们的研究结果支持LRRK2可以调节轴突和树突的生长模式，但它们也表明其作用取决于生长基质和发育阶段。这种可预测的运动变化可以在LRRK2生物测定中利用，并指导LRRK2在体内功能的探索。
Mutations in leucine-rich repeat kinase 2 (LRRK2) underlie an autosomal-dominant form of Parkinson's disease (PD) that is clinically indistinguishable from idiopathic PD. The function of LRRK2 is not well understood, but it has become widely accepted that LRRK2 levels or its kinase activity, which is increased by the most commonly observed mutation (G2019S), regulate neurite growth. However, growth has not been measured; it is not known whether mean differences in length correspond to altered rates of growth or retraction, whether axons or dendrites are impacted differentially or whether effects observed are transient or sustained. To address these questions, we compared several developmental milestones in neurons cultured from mice expressing bacterial artificial chromosome transgenes encoding mouse wildtype-LRRK2 or mutant LRRK2-G2019S, Lrrk2 knockout mice and non-transgenic mice. Over the course of three weeks of development on laminin, the data show a sustained, negative effect of LRRK2-G2019S on dendritic growth and arborization, but counter to expectation, dendrites from Lrrk2 knockout mice do not elaborate more rapidly. In contrast, young neurons cultured on a slower growth substrate, poly-L-lysine, show significantly reduced axonal and dendritic motility in Lrrk2 transgenic neurons and significantly increased motility in Lrrk2 knockout neurons with no significant changes in length. Our findings support that LRRK2 can regulate patterns of axonal and dendritic growth, but they also show that effects vary depending on growth substrate and stage of development. Such predictable changes in motility can be exploited in LRRK2 bioassays and guide exploration of LRRK2 function in vivo.
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影响因子：
11.2
作者：
Biskup, Saskia;Moore, Darren J.;Dawson, Valina L.
通讯作者：
Dawson, Valina L.
影响因子：
4.7
作者：
Gillardon, Frank
通讯作者：
Gillardon, Frank
DOI：
10.1523/jneurosci.4357-09.2009
发表时间：
2009-12-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andres-Mateos E;Mejias R;Sasaki M;Li X;Lin BM;Biskup S;Zhang L;Banerjee R;Thomas B;Yang L;Liu G;Beal MF;Huso DL;Dawson TM;Dawson VL
通讯作者：
Dawson VL
影响因子：
4.2
作者：
MANDELL, JW;BANKER, GA
通讯作者：
BANKER, GA
影响因子：
6.1
作者：
Greggio, Elisa;Jain, Shushant;Cookson, Mark R.
通讯作者：
Cookson, Mark R.