Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research and Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
J Neurosci. 2012 Oct 31;32(44):15565-76. doi: 10.1523/JNEUROSCI.3668-12.2012.
Apoptosis is an essential cellular process in multiple diseases and a major pathway for neuronal death in neurodegeneration. The detailed signaling events/pathways leading to apoptosis, especially in neurons, require further elucidation. Here we identify a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, whose levels are upregulated in brain samples from Alzheimer's disease and infarct patients, and in rodent stroke models, as well as in neurons treated with β-amyloid (Aβ) and glutamate. We further demonstrate that appoptosin induces reactive oxygen species release and intrinsic caspase-dependent apoptosis. The physiological function of appoptosin is to transport/exchange glycine/5-amino-levulinic acid across the mitochondrial membrane for heme synthesis. Downregulation of appoptosin prevents cell death and caspase activation caused by glutamate or Aβ insults. APP modulates appoptosin-mediated apoptosis through interaction with appoptosin. Our study identifies appoptosin as a crucial player in apoptosis and a novel pro-apoptotic protein involved in neuronal cell death, providing a possible new therapeutic target for neurodegenerative disorders.
细胞凋亡是多种疾病中细胞的一种重要的程序性死亡过程，也是神经退行性变中神经元死亡的主要途径。导致细胞凋亡的详细信号事件/途径，特别是在神经元中，需要进一步阐明。在这里，我们鉴定了一种β-淀粉样前体蛋白（APP）相互作用蛋白，命名为凋亡素，其水平在阿尔茨海默病和梗死患者的脑样本中上调，在啮齿动物中风模型中以及在β-淀粉样蛋白（Aβ）和谷氨酸处理的神经元中上调。我们进一步证明凋亡素诱导活性氧的释放和内在半胱天冬酶依赖性凋亡。凋亡素的生理功能是将甘氨酸/5-氨基酮戊酸运出/交换到线粒体膜内，用于血红素合成。下调凋亡素可防止谷氨酸或 Aβ损伤引起的细胞死亡和半胱天冬酶激活。APP 通过与凋亡素相互作用调节凋亡素介导的细胞凋亡。我们的研究将凋亡素鉴定为细胞凋亡中的关键因子和一种新的参与神经元细胞死亡的促凋亡蛋白，为神经退行性疾病提供了一个可能的新的治疗靶点。
