Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
Cell Rep. 2019 Mar 5;26(10):2792-2804.e6. doi: 10.1016/j.celrep.2019.02.027.
VPS10P domain receptors emerge as central regulators of intracellular protein sorting in neurons with relevance for various brain pathologies. Here, we identified a role for the family member SorCS2 in protection of neurons from oxidative stress and epilepsy-induced cell death. We show that SorCS2 acts as sorting receptor that sustains cell surface expression of the neuronal amino acid transporter EAAT3 to facilitate import of cysteine, required for synthesis of the reactive oxygen species scavenger glutathione. Lack of SorCS2 causes depletion of EAAT3 from the plasma membrane and impairs neuronal cysteine uptake. As a consequence, SorCS2-deficient mice exhibit oxidative brain damage that coincides with enhanced neuronal cell death and increased mortality during epilepsy. Our findings highlight a protective role for SorCS2 in neuronal stress response and provide a possible explanation for upregulation of this receptor seen in surviving neurons of the human epileptic brain.
VPS10P 结构域受体是神经元细胞内蛋白质分拣的核心调节因子，与多种脑病理学相关。在这里，我们确定了家族成员 SorCS2 在保护神经元免受氧化应激和癫痫诱导的细胞死亡方面的作用。我们发现 SorCS2 作为分拣受体，维持神经元氨基酸转运体 EAAT3 的细胞表面表达，以促进胱氨酸的摄取，胱氨酸是合成活性氧清除剂谷胱甘肽所必需的。SorCS2 的缺失导致 EAAT3 从质膜中耗尽，并损害神经元胱氨酸摄取。因此，SorCS2 缺陷型小鼠表现出氧化脑损伤，同时伴有神经元细胞死亡增加和癫痫期间死亡率增加。我们的研究结果强调了 SorCS2 在神经元应激反应中的保护作用，并为这种受体在人类癫痫大脑中存活神经元中的上调提供了可能的解释。
