APP upregulation contributes to retinal ganglion cell degeneration via JNK3

Chao Liu, Cheng Wu Zhang, Yi Zhou, Wan Qing Wong, Liying Corinne Lee, Wei Yi Ong, Sung Ok Yoon, Wanjin Hong, Xin Yuan Fu, Tuck Wah Soong, Edward H. Koo, Lawrence W. Stanton, Kah Leong Lim, Zhi-Cheng Xiao, Gavin S. Dawe

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)661-676
Number of pages16
JournalCell Death and Differentiation
Volume25
Issue number4
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • neurological disorders
  • neuroscience

Cite this