LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease.
LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease.
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DOI：
10.1016/j.nbd.2010.04.002
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发表时间：
2010-10
影响因子：
6.1
通讯作者：
Chen SG
中科院分区：
文献类型：
--
作者：
Yao C;El Khoury R;Wang W;Byrd TA;Pehek EA;Thacker C;Zhu X;Smith MA;Wilson-Delfosse AL;Chen SG
迄今为止，LRRK2 突变是常染色体显性遗传和特发性帕金森病 (PD) 的最常见原因，在 GTP 酶 (R1441C/G) 和激酶 (G2019S) 结构域内发现了常见的突变。先前的体外研究表明，R1441C 和 G2019S 突变与激酶活性增加相关。为了更好地了解 LRRK2 相关的 PD 体内发病机制，我们培育了在多巴胺能 (DA) 神经元中过表达人类 LRRK2 野生型、R1441C 和 G2019S 的转基因线虫。这些 LRRK2 蛋白的过度表达会导致年龄依赖性 DA 神经变性、行为缺陷和运动功能障碍，并伴有体内多巴胺水平降低。相比之下，R1441C 和 G2019S 突变体比野生型蛋白引起更严重的表型。有趣的是，外源多巴胺治疗可以挽救 LRRK2 诱导的行为和运动表型。相反，GTP 结合缺陷突变体 K1347A 的表达或线虫 LRRK2 同源物 LRK-1 的敲除可防止 LRRK2 诱导的神经变性和行为异常。因此，我们的转基因 LRRK2 线虫模型概括了 PD 的关键特征，包括进行性神经变性、多巴胺依赖性行为和运动功能受损以及多巴胺水平降低。此外，我们的研究结果为 GTP 酶/激酶活性在 LRRK2 相关病理学中的关键作用提供了强有力的支持。这些无脊椎动物模型将有助于研究帕金森病的发病机制和开发该疾病的潜在疗法。
Mutations in LRRK2 are thus far the most frequent known cause of autosomal dominant and idiopathic Parkinson’s disease (PD) with prevalent mutations being found within the GTPase (R1441C/G) and kinase (G2019S) domains. Previous in vitro studies have revealed that R1441C and G2019S mutations are associated with increased kinase activity. To better understand LRRK2-linked PD pathogenesis in vivo, we have generated transgenic C. elegans overexpressing human LRRK2 wild type, R1441C and G2019S in dopaminergic (DA) neurons. Overexpression of these LRRK2 proteins causes age-dependent DA neurodegeneration, behavioral deficits, and locomotor dysfunction that are accompanied by a reduction of dopamine levels in vivo. In comparison, R1441C and G2019S mutants cause more severe phenotypes than the wild type protein. Interestingly, treatment with exogenous dopamine rescues the LRRK2-induced behavioral and locomotor phenotypes. In contrast, expression of the GTP binding defective mutant, K1347A, or knockout of the C. elegans LRRK2 homolog, LRK-1, prevents the LRRK2-induced neurodegeneration and behavioral abnormalities. Hence, our transgenic LRRK2 C. elegans models recapitulate key features of PD including progressive neurodegeneration, impairment of dopamine-dependent behavior and locomotor function, and reduction in dopamine levels. Furthermore, our findings provide strong support for the critical role of GTPase/kinase activity in LRRK2-linked pathologies. These invertebrate models will be useful for studying pathogenesis of PD and for development of potential therapeutics for the disease.
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影响因子：
3
作者：
Feng Z;Cronin CJ;Wittig JH Jr;Sternberg PW;Schafer WR
通讯作者：
Schafer WR
影响因子：
4.2
作者：
Gandhi, Payal N.;Chen, Shu G.;Wilson-Delfosse, Amy L.
通讯作者：
Wilson-Delfosse, Amy L.
影响因子：
25
作者：
Li, Yanping;Liu, Wencheng;Oo, Tinmarla F.;Wang, Lei;Tang, Yi;Jackson-Lewis, Vernice;Zhou, Chun;Geghman, Kindiya;Bogdanov, Mikhail;Przedborski, Serge;Beal, M. Flint;Burke, Robert E.;Li, Chenjian
通讯作者：
Li, Chenjian
影响因子：
4.8
作者：
Saermann, Julia;Hegermann, Jan;Schmidt, Enrico
通讯作者：
Schmidt, Enrico
影响因子：
4.7
作者：
Artal-Sanz, Marto;de Jong, Liesbeth;Tavernarakis, Nektarios
通讯作者：
Tavernarakis, Nektarios