Department of Protein Science and Institute of Developmental Genetics, Helmholtz Zentrum München, D-85764 Munich, Germany.
J Neurosci. 2011 Feb 9;31(6):2225-37. doi: 10.1523/JNEUROSCI.3730-10.2011.
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.
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。
