Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24503-24513. doi: 10.1073/pnas.2004087117. Epub 2020 Sep 14.
The Hippo (MST1/2) pathway plays a critical role in restricting tissue growth in adults and modulating cell proliferation, differentiation, and migration in developing organs. Netrin1, a secreted laminin-related protein, is essential for nervous system development. However, the mechanisms underlying MST1 regulation by the extrinsic signals remain unclear. Here, we demonstrate that Netrin1 reduction in Parkinson's disease (PD) activates MST1, which selectively binds and phosphorylates netrin receptor UNC5B on T428 residue, promoting its apoptotic activation and dopaminergic neuronal loss. Netrin1 deprivation stimulates MST1 activation and interaction with UNC5B, diminishing YAP levels and escalating cell deaths. Knockout of UNC5B abolishes netrin depletion-induced dopaminergic loss, whereas blockade of MST1 phosphorylating UNC5B suppresses neuronal apoptosis. Remarkably, Netrin1 is reduced in PD patient brains, associated with MST1 activation and UNC5B T428 phosphorylation, which is accompanied by YAP reduction and apoptotic activation. Hence, Netrin1 regulates Hippo (MST1) pathway in dopaminergic neuronal loss in PD via UNC5B receptor.
Hippo（MST1/2）通路在限制成年人组织生长和调节发育器官中的细胞增殖、分化和迁移方面发挥着关键作用。Netrin1 是一种分泌的层粘连蛋白相关蛋白，对神经系统的发育至关重要。然而，外在信号调节 MST1 的机制尚不清楚。在这里，我们证明帕金森病（PD）中 Netrin1 的减少会激活 MST1，MST1 选择性地结合并磷酸化 Netrin 受体 UNC5B 的 T428 残基，促进其凋亡激活和多巴胺能神经元丢失。Netrin1 的剥夺会刺激 MST1 的激活和与 UNC5B 的相互作用，降低 YAP 水平并增加细胞死亡。UNC5B 的敲除会消除 Netrin 耗竭诱导的多巴胺能神经元丢失，而抑制 MST1 磷酸化 UNC5B 可抑制神经元凋亡。值得注意的是，PD 患者大脑中的 Netrin1 减少与 MST1 激活和 UNC5B T428 磷酸化有关，这伴随着 YAP 减少和凋亡激活。因此，Netrin1 通过 UNC5B 受体调节 PD 中多巴胺能神经元丢失中的 Hippo（MST1）通路。
