Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.
Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.
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DOI：
10.1016/j.neuron.2009.11.006
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发表时间：
2009-12-24
期刊：
影响因子：
16.2
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
--
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
α-突触核蛋白和富含亮氨酸重复序列激酶2（LRRK 2）的突变与帕金森病（PD）的常染色体显性形式有关。然而，很少有人知道这两个PD相关基因之间的任何潜在的病理生理相互作用。我们在转基因小鼠中发现，尽管LRRK 2单独过表达不会引起神经退行性变，但过量LRRK 2的存在大大加速了PD相关A53 T α-突触核蛋白转基因小鼠中神经病理学异常的进展。此外，我们发现LRRK 2促进了A53 T小鼠体内α-synuclein的异常聚集和体细胞积累，这可能是由于微管动力学、高尔基体组织和泛素-蛋白酶体通路受损所致。相反，LRRK 2的基因切除保留了高尔基体结构，抑制了α-突触核蛋白的聚集和体细胞积累，从而延缓了A53 T小鼠神经病理学的进展。这些发现表明，LRRK 2的过表达增强了α-突触核蛋白介导的细胞毒性，并表明抑制LRRK 2表达是改善α-突触核蛋白诱导的神经变性的潜在治疗选择。
Mutations in α-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson’s disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although over-expression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T α-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of α-synuclein in A53T mice, likely resulted from the impairment of microtubule dynamics, Golgi organization, and ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure, suppressed the aggregation and somatic accumulation of α-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that over-expression of LRRK2 enhances α-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating α-synuclein-induced neurodegeneration.
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影响因子：
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作者：
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