APP upregulation contributes to retinal ganglion cell degeneration via JNK3

被引：24

作者：

Liu, Chao ^{[1
,2
,3
,4
]}

Zhang, Cheng-Wu ^{[5
,6
,7
]}

Zhou, Yi ^{[2
,8
]}

Wong, Wan Qing ^{[1
,2
,3
,9
]}

Lee, Liying Corinne ^{[4
]}

Ong, Wei Yi ^{[2
,10
]}

Yoon, Sung Ok ^{[11
]}

Hong, Wanjin ^{[12
]}

Fu, Xin-Yuan ^{[2
,8
]}

Soong, Tuck Wah ^{[2
,4
]}

Koo, Edward H. ^{[4
,13
]}

Stanton, Lawrence W. ^{[9
]}

Lim, Kah-Leong ^{[2
,4
,7
]}

Xiao, Zhi-Cheng ^{[14
,15
]}

Dawe, Gavin S. ^{[1
,2
,3
]}

机构：

[1] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Pharmacol, 16 Med Dr, Singapore 117600, Singapore

[2] Natl Univ Singapore, Life Sci Inst, Ctr Life Sci, Neurobiol & Ageing Programme, 28 Med Dr, Singapore 117456, Singapore

[3] Natl Univ Singapore, Singapore Inst Neurotechnol SINAPSE, Ctr Life Sci, 28 Med Dr, Singapore 117456, Singapore

[4] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Physiol, 2 Med Dr, Singapore 117597, Singapore

[5] Nanjing Tech Univ Nanjing Tech, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, Key Lab Flexible Elect KLOFE, 30 South Puzhu Rd, Nanjing 211816, Jiangsu, Peoples R China

[6] Nanjing Tech Univ Nanjing Tech, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, IAM, 30 South Puzhu Rd, Nanjing 211816, Jiangsu, Peoples R China

[7] Natl Neurosci Inst, Neurodegenerat Res Lab, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore

[8] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Biochem, 8 Med Dr, Singapore 117596, Singapore

[9] Genome Inst Singapore, Stem Cell & Regenerat Biol Grp, 60 Biopolis St, Singapore 138672, Singapore

[10] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Anat, 4 Med Dr, Singapore 117594, Singapore

[11] Ohio State Univ, Dept Biol Chem & Pharmacol, Wexner Med Ctr, Columbus, OH 43210 USA

[12] ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore

[13] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, 12 Sci Dr 2, Singapore 117549, Singapore

[14] Monash Univ Clayton, Dept Anat & Dev Biol, Melbourne, Vic 3800, Australia

[15] Kunming Med Coll, Inst Mol & Clin Med, Key Lab Stem Cell & Regenerat Med, Kunming 650031, Yunnan, Peoples R China

来源：

CELL DEATH AND DIFFERENTIATION | 2018年 / 25卷 / 04期

基金：

英国医学研究理事会;

关键词：

AMYLOID PRECURSOR PROTEIN; OPTIC-NERVE TRANSECTION; INTRACELLULAR DOMAIN; TRANSGENIC MICE; AXONAL INJURY; ADULT-RATS; PATHOLOGICAL FEATURES; OCULAR HYPERTENSION; ALZHEIMERS-DISEASE; POSSIBLE TARGET;

D O I：

10.1038/s41418-017-0005-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：661 / 676

页数：16

共 60 条

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