68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment.
68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment.
复制标题
68和FX2149减弱突变体LRRK2-R1441C诱导的神经运输障碍。
DOI：
10.3389/fnagi.2016.00337
复制
发表时间：
2016
影响因子：
4.8
通讯作者：
Smith WW
中科院分区：
文献类型：
--
作者：
Thomas JM;Li T;Yang W;Xue F;Fishman PS;Smith WW
富含亮氨酸的重复序列激酶2是一种大的蛋白质，与帕金森病的遗传和散发性病因有关。LRRK 2的生理功能在很大程度上是未知的。在这份报告中，我们研究了LRRK 2是否改变神经运输使用活细胞成像技术和人神经母细胞瘤SH-SY 5 Y细胞。我们的研究结果表明，PD连锁突变体，LRRK 2-R1441 C，诱导SH-SY 5 Y细胞的神经突的线粒体和溶酶体运输缺陷的表达。最重要的是，最近鉴定的GTP结合抑制剂68和FX 2149可以降低LRRK 2 GTP结合活性并减弱R1441 C诱导的线粒体和溶酶体转运障碍。这些结果为LRRK 2诱导的神经退行性变的神经突损伤提供了直接证据和早期机制。这是第一份报告表明，LRRK 2 GTP结合活性在神经突转运过程中起着关键作用，表明抑制LRRK 2 GTP结合可能是PD干预的潜在新策略。
Leucine-rich repeat kinase 2 is a large protein with implications in genetic and sporadic causes of Parkinson's disease. The physiological functions of LRRK2 are largely unknown. In this report, we investigated whether LRRK2 alters neural transport using live-cell imaging techniques and human neuroblastoma SH-SY5Y cells. Our results demonstrated that expression of the PD-linked mutant, LRRK2-R1441C, induced mitochondrial, and lysosomal transport defects in neurites of SH-SY5Y cells. Most importantly, recently identified GTP-binding inhibitors, 68 and FX2149, can reduce LRRK2 GTP-binding activity and attenuates R1441C-induced mitochondrial and lysosomal transport impairments. These results provide direct evidence and an early mechanism for neurite injury underlying LRRK2-induced neurodegeneration. This is the first report to show that LRRK2 GTP-binding activity plays a critical role during neurite transport, suggesting inhibition of LRRK2 GTP-binding could be a potential novel strategy for PD intervention.