LRRK2 控制着循环池内突触囊泡的储存和转运。
LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
机构信息
Department of Protein Science and Institute of Developmental Genetics, Helmholtz Zentrum München, D-85764 Munich, Germany.
出版信息
J Neurosci. 2011 Feb 9;31(6):2225-37. doi: 10.1523/JNEUROSCI.3730-10.2011.
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the single most common cause of inherited Parkinson's disease. Little is known about its involvement in the pathogenesis of Parkinson's disease mainly because of the lack of knowledge about the physiological role of LRRK2. To determine the function of LRRK2, we studied the impact of short hairpin RNA-mediated silencing of LRRK2 expression in cortical neurons. Paired recording indicated that LRRK2 silencing affects evoked postsynaptic currents. Furthermore, LRRK2 silencing induces at the presynaptic site a redistribution of vesicles within the bouton, altered recycling dynamics, and increased vesicle kinetics. Accordingly, LRRK2 protein is present in the synaptosomal compartment of cortical neurons in which it interacts with several proteins involved in vesicular recycling. Our results suggest that LRRK2 modulates synaptic vesicle trafficking and distribution in neurons and in consequence participates in regulating the dynamics between vesicle pools inside the presynaptic bouton.
摘要
LRRK2（富含亮氨酸重复激酶 2）突变是导致遗传性帕金森病的最常见原因。由于对 LRRK2 的生理作用缺乏了解，因此其在帕金森病发病机制中的作用知之甚少。为了确定 LRRK2 的功能，我们研究了短发夹 RNA 介导的 LRRK2 表达沉默对皮质神经元的影响。成对记录表明，LRRK2 沉默会影响诱发的突触后电流。此外，LRRK2 沉默会诱导囊泡在触突内的再分布、改变循环动力学，并增加囊泡动力学。因此，LRRK2 蛋白存在于皮质神经元的突触小体部分，它与参与囊泡循环的几种蛋白质相互作用。我们的研究结果表明，LRRK2 调节神经元中突触囊泡的运输和分布，从而参与调节突触前触突内囊泡库之间的动力学。
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本文引用的文献
1
An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database.一种将肽的串联质谱数据与蛋白质数据库中氨基酸序列相关联的方法。
J Am Soc Mass Spectrom. 1994 Nov;5(11):976-89. doi: 10.1016/1044-0305(94)80016-2.
2
Reevaluation of phosphorylation sites in the Parkinson disease-associated leucine-rich repeat kinase 2.帕金森病相关富亮氨酸重复激酶 2 中磷酸化位点的再评价。
J Biol Chem. 2010 Sep 17;285(38):29569-76. doi: 10.1074/jbc.M110.127639. Epub 2010 Jul 1.
3
Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect.LRRK2 的 WD40 结构域缺失导致斑马鱼帕金森样神经元丢失和运动缺陷。
PLoS Genet. 2010 Apr 22;6(4):e1000914. doi: 10.1371/journal.pgen.1000914.
4
Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release.快速的活性区结构改变导致神经递质释放的持续变化。
Proc Natl Acad Sci U S A. 2010 May 11;107(19):8836-41. doi: 10.1073/pnas.0906087107. Epub 2010 Apr 26.
5
Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.α-突触核蛋白表达增加通过抑制内吞作用后突触囊泡再聚集减少神经递质释放。
Neuron. 2010 Jan 14;65(1):66-79. doi: 10.1016/j.neuron.2009.12.023.
6
Leucine-rich repeat kinase 2 induces alpha-synuclein expression via the extracellular signal-regulated kinase pathway.富含亮氨酸重复激酶 2 通过细胞外信号调节激酶通路诱导α-突触核蛋白表达。
Cell Signal. 2010 May;22(5):821-7. doi: 10.1016/j.cellsig.2010.01.006. Epub 2010 Jan 13.
7
Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.富含亮氨酸重复激酶 2 调节帕金森病相关突变型 α-突触核蛋白诱导的神经病理学进展。
Neuron. 2009 Dec 24;64(6):807-27. doi: 10.1016/j.neuron.2009.11.006.
8
The WD40 domain is required for LRRK2 neurotoxicity.WD40 结构域对于 LRRK2 的神经毒性是必需的。
PLoS One. 2009 Dec 24;4(12):e8463. doi: 10.1371/journal.pone.0008463.
9
Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).LRRK2 敲除小鼠对 MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）的超敏反应缺失出乎意料。
J Neurosci. 2009 Dec 16;29(50):15846-50. doi: 10.1523/JNEUROSCI.4357-09.2009.
10
Molecular mechanisms determining conserved properties of short-term synaptic depression revealed in NSF and SNAP-25 conditional mutants.在 NSF 和 SNAP-25 条件突变体中揭示的决定短期突触抑制保守特性的分子机制。
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14658-63. doi: 10.1073/pnas.0907144106. Epub 2009 Aug 11.
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