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Title: APP upregulation contributes to retinal ganglion cell degeneration via JNK3
Authors: Liu C. 
Zhang C.-W.
Zhou Y. 
Wong W.Q.
Lee L.C. 
Ong W.Y. 
Yoon S.O.
Hong W.
Fu X.-Y. 
Soong T.W. 
Koo E.H. 
Stanton L.W.
Lim K.-L. 
Xiao Z.-C.
Dawe G.S. 
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Liu C., Zhang C.-W., Zhou Y., Wong W.Q., Lee L.C., Ong W.Y., Yoon S.O., Hong W., Fu X.-Y., Soong T.W., Koo E.H., Stanton L.W., Lim K.-L., Xiao Z.-C., Dawe G.S. (2018). APP upregulation contributes to retinal ganglion cell degeneration via JNK3. Cell Death Differ. 25 (4) : 661-676. ScholarBank@NUS Repository.
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. © 2017 ADMC Associazione Differenziamento e Morte Cellulare.
Source Title: Cell Death Differ.
ISSN: 13509047
DOI: 10.1038/s41418-017-0005-3
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