Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, South Korea.
Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, South Korea.
Glia. 2021 Sep;69(9):2133-2145. doi: 10.1002/glia.24013. Epub 2021 May 6.
Our recent finding has demonstrated that astrocytes confer neuroprotection by endogenously producing ciliary neurotrophic factor (CNTF) via transient receptor potential vanilloid 1 (TRPV1) in Parkinson's disease (PD). In this study, the possible molecular target for TRPV1-mediated CNTF production and its neuroprotective effects on dopamine neurons were further investigated. For comparison, glial cell-line derived neurotrophic factor (GDNF) was also examined. The results show that TRPV1-ribosomal protein 70 S6 kinase (p70S6K) signaling on astrocytes produces endogenous CNTF in the SN of MPP -lesioned rat. By marked contrast, the expression of GDNF on astrocytes is independent of TRPV1-p70S6K signaling. Administration of a TRPV1 agonist, capsaicin, increases levels of phosphorylated p70S6K (p-p70S6K; activation of p70S6K) on astrocytes, resulting in the survival of dopamine neurons and behavioral recovery through endogenous production of CNTF in the MPP -lesioned rat model of PD. Immunohistochemical analysis reveals expression of p-p70S6K on astrocytes in the SN of PD patients, indicating relevance to human PD. The present in vivo data is the first to demonstrate that astrocytic TRPV1-p70S6K signaling plays a pivotal role as endogenous neuroprotective, and it may constitute a novel therapeutic target for treating PD.
我们最近的发现表明，星形胶质细胞通过瞬时受体电位香草酸 1（TRPV1）在帕金森病（PD）中内源性产生睫状神经营养因子（CNTF）来发挥神经保护作用。在这项研究中，进一步研究了 TRPV1 介导的 CNTF 产生的可能分子靶标及其对多巴胺神经元的神经保护作用。为了进行比较，还研究了神经胶质细胞衍生的神经营养因子（GDNF）。结果表明，星形胶质细胞上的 TRPV1-核糖体蛋白 70 S6 激酶（p70S6K）信号转导在 MPP 损伤的大鼠 SN 中产生内源性 CNTF。相比之下，星形胶质细胞上的 GDNF 的表达独立于 TRPV1-p70S6K 信号转导。TRPV1 激动剂辣椒素的给药增加了星形胶质细胞中磷酸化 p70S6K（p-p70S6K；p70S6K 的激活）的水平，导致多巴胺神经元的存活和行为恢复，这是通过 PD 的 MPP 损伤大鼠模型中内源性 CNTF 的产生实现的。免疫组织化学分析显示 PD 患者 SN 中星形胶质细胞上存在 p-p70S6K 的表达，表明与人类 PD 相关。本体内数据首次表明，星形胶质细胞 TRPV1-p70S6K 信号转导作为内源性神经保护作用发挥着关键作用，它可能构成治疗 PD 的新的治疗靶标。
