AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression
AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression
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DOI：
10.1186/s40035-018-0106-z
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发表时间：
2018-01-23
影响因子：
12.6
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
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作者：
Cho, Hyun Jin;Xie, Chengsong;Cai, Huaibin
背景：富含亮氨酸重复序列激酶2（LRRK 2）突变是散发性和家族性帕金森病（PD）最常见的遗传原因。特别是LRRK 2 G2019 S错义突变已被确定为晚发性PD中最常见的遗传原因。晚期糖基化终末产物（AGEs）在糖尿病和多种与衰老相关的疾病（如心血管疾病、肾脏疾病和神经系统疾病）中大量产生。AGEs触发与氧化应激和炎症以及细胞死亡相关的细胞内信号通路。AGEs的受体β 1通过与AGEs相互作用而被激活，并介导AGEs诱导的细胞毒性。无论是AGE和AGEs参与突变型LRRK2.Methods的发病机制是未知的：使用细胞系转染突变型LRRK 2以及来自LRRK 2野生型（WT）和G2019 S转基因小鼠的原代神经元培养物，我们比较了AGE治疗的影响，通过免疫染色的控制和突变细胞的生存。我们还研究了在转基因小鼠和PD患者的大脑中的蛋白质的水平通过western blots.Results：我们表明，LRRK 2 G2019 S突变体表达的神经元更敏感的AGE诱导的细胞死亡相比，控制。此外，我们发现，在LRRK 2 G2019 S突变cells.Conclusions：这些数据表明，增强的AGE-E2相互作用有助于LRRK 2 G2019 S突变介导的进行性神经元丢失在PD中的水平上调。
Background: Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson's disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation end products (AGEs) are produced in high amounts in diabetes and diverse aging-related disorders, such as cardiovascular disease, renal disease, and neurological disease. AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death. RAGE, receptor of AGEs, is activated by interaction with AGEs and mediates AGE-induced cytotoxicity. Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown.Methods: Using cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type (WT) and G2019S transgenic mice, we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining. We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots.Results: We show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls. Furthermore, we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells.Conclusions: These data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD.