Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease.
Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease.
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DOI：
10.1186/1742-2094-11-86
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发表时间：
2014-05-08
影响因子：
9.3
通讯作者：
Hartmann A
中科院分区：
文献类型：
--
作者：
Noelker C;Morel L;Osterloh A;Alvarez-Fischer D;Lescot T;Breloer M;Gold M;Oertel WH;Henze C;Michel PP;Dodel RC;Lu L;Hirsch EC;Hunot S;Hartmann A
越来越多的证据表明，帕金森病 (PD) 患者黑质 (SN) 中与小胶质细胞激活相关的炎症不仅是神经元变性的结果，而且随着时间的推移，可能会主动维持多巴胺能 (DA) 细胞的损失。我们的目的是研究细胞内伴侣热休克蛋白 60 (Hsp60) 是否可以作为中枢神经系统损伤的信号来激活小胶质细胞。测量用 MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）治疗的 C57/BL6 小鼠中脑和纹状体中 Hsp60 mRNA 的表达量，以及 PD 患者和年龄匹配受试者 SN 中 Hsp60/TH mRNA 的比率。为了进一步研究神经元 Hsp60 反应与 PD 相关细胞应激之间可能的联系，与对照细胞相比，在不同时间点（6、12、24 和 48 小时）用 100 μM MPP+（1-甲基-4-苯基吡啶鎓）处理后，对 SH-SY5Y 的细胞裂解物进行 Hsp60 免疫印迹分析和定量。使用额外的 MTT 和 LDH 测定。接下来我们解决了以下问题：在用 MPP+ (1 μM)、hHsp60 (10 μg/ml) 或两者组合处理的中脑神经元-胶质细胞培养物中，Hsp60 是否影响 TH+ 神经元的存活。最后，我们通过 ELISA 测量了用不同 hHsp60 制剂处理后的原代小胶质细胞培养物中的 IL-1β、IL-6、TNF-α 和 NO 释放。对照培养物暴露于LPS。在接受 MPTP 治疗的小鼠的中脑和纹状体以及 PD 患者的 SN 中，我们发现 Hsp60 mRNA 上调。 MPP+（MPTP 的活性代谢物）也会导致人多巴胺能细胞系 SH-SY5Y 中 Hsp60 的表达和释放增加。有趣的是，除了对原代中脑培养物中的 DA 神经元具有毒性外，外源性 Hsp60 还加剧了 MPP+ 的影响。然而，尽管我们证明 Hsp60 特异性结合小胶质细胞，但它未能刺激这些细胞产生促炎细胞因子或 NO。总体而言，我们的数据表明 Hsp60 可能参与 PD 中的 DA 细胞死亡，但通过与细胞因子释放无关的机制。
Increasing evidence suggests that inflammation associated with microglial cell activation in the substantia nigra (SN) of patients with Parkinson disease (PD) is not only a consequence of neuronal degeneration, but may actively sustain dopaminergic (DA) cell loss over time. We aimed to study whether the intracellular chaperone heat shock protein 60 (Hsp60) could serve as a signal of CNS injury for activation of microglial cells. Hsp60 mRNA expression in the mesencephalon and the striatum of C57/BL6 mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and the Hsp60/TH mRNA ratios in the SN of PD patients and aged-matched subjects were measured. To further investigate a possible link between the neuronal Hsp60 response and PD-related cellular stress, Hsp60 immunoblot analysis and quantification in cell lysates from SH-SY5Y after treatment with 100 μM MPP+ (1-methyl-4-phenylpyridinium) at different time points (6, 12, 24 and 48 hours) compared to control cells were performed. Additional MTT and LDH assay were used. We next addressed the question as to whether Hsp60 influences the survival of TH+ neurons in mesencephalic neuron-glia cultures treated either with MPP+ (1 μM), hHsp60 (10 μg/ml) or a combination of both. Finally, we measured IL-1β, IL-6, TNF-α and NO-release by ELISA in primary microglial cell cultures following treatment with different hHsp60 preparations. Control cultures were exposed to LPS. In the mesencephalon and striatum of mice treated with MPTP and also in the SN of PD patients, we found that Hsp60 mRNA was up-regulated. MPP+, the active metabolite of MPTP, also caused an increased expression and release of Hsp60 in the human dopaminergic cell line SH-SY5Y. Interestingly, in addition to being toxic to DA neurons in primary mesencephalic cultures, exogenous Hsp60 aggravated the effects of MPP+. Yet, although we demonstrated that Hsp60 specifically binds to microglial cells, it failed to stimulate the production of pro-inflammatory cytokines or NO by these cells. Overall, our data suggest that Hsp60 is likely to participate in DA cell death in PD but via a mechanism unrelated to cytokine release.
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影响因子：
14.8
作者：
Jackson-Lewis, Vernice;Przedborski, Serge
通讯作者：
Przedborski, Serge
影响因子：
4.4
作者：
Flohé, SB;Brüggemann, J;Kolb, H
通讯作者：
Kolb, H
影响因子：
4.4
作者：
Habich, C;Baumgart, K;Burkart, V
通讯作者：
Burkart, V
影响因子：
4.3
作者：
Barreto, A;Gonzalez, JM;Fiorentino, S
通讯作者：
Fiorentino, S
影响因子：
3.5
作者：
AMANO, F;NODA, T
通讯作者：
NODA, T