APP upregulation contributes to retinal ganglion cell degeneration via JNK3.
APP upregulation contributes to retinal ganglion cell degeneration via JNK3.
复制标题
DOI：
10.1038/s41418-017-0005-3
复制
发表时间：
2018-03
影响因子：
12.4
通讯作者：
Dawe GS
中科院分区：
文献类型：
--
作者：
Liu C;Zhang CW;Zhou Y;Wong WQ;Lee LC;Ong WY;Yoon SO;Hong W;Fu XY;Soong TW;Koo EH;Stanton LW;Lim KL;Xiao ZC;Dawe GS
轴索损伤是中枢神经系统损伤的常见特征。在中枢神经系统神经创伤后观察到淀粉样前体蛋白（APP）的上调，并将其视为中枢神经系统轴突损伤的标志物。然而，APP介导神经元死亡的潜在机制仍有待阐明。在这里，我们使用小鼠视神经轴突切断术（ONA）来模拟中枢神经系统轴突损伤，复制视神经病中视网膜神经节细胞（RGC）死亡的方面。在ONA和APP敲除减少Tuj 1 + RGC丢失后，APP和APP胞内结构域（AICD）在视网膜中上调。结合染色质免疫沉淀和荧光素酶报告基因分析的微阵列数据的通路分析表明，AICD与JNK 3基因位点相互作用，并调节JNK 3的表达。此外，发现JNK 3在ONA后上调，并导致Tuj 1 + RGC死亡。APP敲除可降低ONA诱导的JNK 3和磷酸化JNK（pJNK）表达增强。γ-分泌酶抑制剂阻止AICD的产生，类似地降低JNK 3和pJNK表达，并保护Tuj 1 + RGCs免受ONA诱导的细胞死亡。这些数据共同表明，ONA诱导APP表达，APP的γ-分泌酶裂解释放AICD，其上调JNK 3，导致RGC死亡。该途径可能是视神经病和其他形式神经创伤中神经元保护的新靶点。
Axonal injury is a common feature of central nervous system insults. Upregulation of amyloid precursor protein (APP) is observed following central nervous system neurotrauma and is regarded as a marker of central nervous system axonal injury. However, the underlying mechanism by which APP mediates neuronal death remains to be elucidated. Here, we used mouse optic nerve axotomy (ONA) to model central nervous system axonal injury replicating aspects of retinal ganglion cell (RGC) death in optic neuropathies. APP and APP intracellular domain (AICD) were upregulated in retina after ONA and APP knockout reduced Tuj1+ RGC loss. Pathway analysis of microarray data combined with chromatin immunoprecipitation and a luciferase reporter assay demonstrated that AICD interacts with the JNK3 gene locus and regulates JNK3 expression. Moreover, JNK3 was found to be upregulated after ONA and to contribute to Tuj1+ RGC death. APP knockout reduced the ONA-induced enhanced expression of JNK3 and phosphorylated JNK (pJNK). Gamma-secretase inhibitors prevented production of AICD, reduced JNK3 and pJNK expression similarly, and protected Tuj1+ RGCs from ONA-induced cell death. Together these data indicate that ONA induces APP expression and that gamma-secretase cleavage of APP releases AICD, which upregulates JNK3 leading to RGC death. This pathway may be a novel target for neuronal protection in optic neuropathies and other forms of neurotrauma.
登录
查看更多内容
DOI：
10.1097/nen.0b013e3181db8100
发表时间：
2010-05
影响因子：
3.2
作者：
Choi WS;Abel G;Klintworth H;Flavell RA;Xia Z
通讯作者：
Xia Z
影响因子：
6.1
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Fornarola, Laura B.;Freeman, Robert S.;Clark, Abbot F.;Pang, Iok-Hou;John, Simon W. M.;Libby, Richard T.
通讯作者：
Libby, Richard T.
影响因子：
9.3
作者：
Christensen DP;Ejlerskov P;Rasmussen I;Vilhardt F
通讯作者：
Vilhardt F
影响因子：
56.9
作者：
Cao, XW;Südhof, TC
通讯作者：
Südhof, TC
DOI：
10.1073/pnas.87.4.1561
发表时间：
1990-02-01
影响因子：
11.1
作者：
KOO, EH;SISODIA, SS;PRICE, DL
通讯作者：
PRICE, DL