Institute of Biotechnology, HiLIFE, University of Helsinki, 00790 Helsinki, Finland.
Int J Mol Sci. 2022 Aug 22;23(16):9489. doi: 10.3390/ijms23169489.
Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that has beneficial effects on dopamine neurons in both in vitro and in vivo models of Parkinson's disease (PD). CDNF was recently tested in phase I-II clinical trials for the treatment of PD, but the mechanisms underlying its neuroprotective properties are still poorly understood, although studies have suggested its role in the regulation of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR). The aim of this study was to investigate the mechanism of action of CDNF through analyzing the involvement of UPR signaling in its anti-apoptotic function. We used tunicamycin to induce ER stress in mice in vivo and used cultured primary neurons and found that CDNF expression is regulated by ER stress in vivo and that the involvement of UPR pathways is important for the neuroprotective function of CDNF. Moreover, we used AP-MS and BiFC to perform the first interactome screening for CDNF and report novel binding partners of CDNF. These findings allowed us to hypothesize that CDNF protects neurons from ER-stress-inducing agents by modulating UPR signaling towards cell survival outcomes.
脑源性神经营养因子（CDNF）是一种神经营养因子，在帕金森病（PD）的体外和体内模型中对多巴胺神经元均具有有益作用。CDNF 最近在治疗 PD 的 I 期- II 期临床试验中进行了测试，但它的神经保护特性的机制仍知之甚少，尽管研究表明其在调节内质网（ER）稳态和未折叠蛋白反应（UPR）中的作用。本研究旨在通过分析 UPR 信号通路在其抗细胞凋亡功能中的参与，来研究 CDNF 的作用机制。我们使用衣霉素在体内诱导 ER 应激，并使用培养的原代神经元，发现 CDNF 的表达受体内 ER 应激的调节，而 UPR 途径的参与对于 CDNF 的神经保护功能很重要。此外，我们使用 AP-MS 和 BiFC 进行了 CDNF 的首次互作组筛选，并报告了 CDNF 的新结合伴侣。这些发现使我们假设 CDNF 通过调节 UPR 信号转导以产生细胞存活结果来保护神经元免受 ER 应激诱导剂的影响。
