SorCS2 调节多巴胺能神经布线，并在外周神经胶质中被加工成凋亡的双链受体。

SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia.

机构信息

The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

出版信息

Neuron. 2014 Jun 4;82(5):1074-87. doi: 10.1016/j.neuron.2014.04.022.

DOI:10.1016/j.neuron.2014.04.022

PMID:24908487

Abstract

Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.

摘要

平衡营养和凋亡信号对于神经元回路的发育和再生至关重要。在这里，我们鉴定出 SorCS2 是一种神经营养素前体 (proNT) 受体，与 p75(NTR) 一起介导营养和凋亡信号。中枢神经系统神经元而不是神经胶质细胞表达 SorCS2 作为一种单链蛋白，对于 proBDNF 诱导的多巴胺能过程中的生长锥塌陷是必需的。SorCS2 或 p75(NTR) 缺失的小鼠导致多巴胺水平和代谢降低，以及额皮质多巴胺能过度支配。相应地，两种敲除模型对安非他命表现出类似于 ADHD 的矛盾行为反应。相反，在 PNS 神经胶质细胞中，但不在神经元中，蛋白水解处理产生了一种介导 proNT 依赖性施万细胞凋亡的 SorCS2 双体形式。坐骨神经损伤触发了 p75(NTR) 阳性死亡施万细胞中双链 SorCS2 的产生，而 Sorcs2(-/-) 小鼠中的凋亡则明显减弱。总之，我们已经证明，SorCS2 的双链体加工使神经元和神经胶质细胞对神经营养素前体产生不同的反应。