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 language | English |
|---|---|
| Pages (from-to) | 661-676 |
| Number of pages | 16 |
| Journal | Cell Death and Differentiation |
| Volume | 25 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 1 Mar 2018 |
Keywords
- neurological disorders
- neuroscience
Cite this
}
APP upregulation contributes to retinal ganglion cell degeneration via JNK3. / Liu, Chao; Zhang, Cheng Wu; Zhou, Yi; Wong, Wan Qing; Lee, Liying Corinne; Ong, Wei Yi; Yoon, Sung Ok; Hong, Wanjin; Fu, Xin Yuan; Soong, Tuck Wah; Koo, Edward H.; Stanton, Lawrence W.; Lim, Kah Leong; Xiao, Zhi-Cheng; Dawe, Gavin S.
In: Cell Death and Differentiation, Vol. 25, No. 4, 01.03.2018, p. 661-676.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - APP upregulation contributes to retinal ganglion cell degeneration via JNK3
AU - Liu, Chao
AU - Zhang, Cheng Wu
AU - Zhou, Yi
AU - Wong, Wan Qing
AU - Lee, Liying Corinne
AU - Ong, Wei Yi
AU - Yoon, Sung Ok
AU - Hong, Wanjin
AU - Fu, Xin Yuan
AU - Soong, Tuck Wah
AU - Koo, Edward H.
AU - Stanton, Lawrence W.
AU - Lim, Kah Leong
AU - Xiao, Zhi-Cheng
AU - Dawe, Gavin S.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - neurological disorders
KW - neuroscience
UR - http://www.scopus.com/inward/record.url?scp=85037991652&partnerID=8YFLogxK
U2 - 10.1038/s41418-017-0005-3
DO - 10.1038/s41418-017-0005-3
M3 - Article
VL - 25
SP - 661
EP - 676
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 4
ER -