Abstract
The cJun N-terminal kinases (JNKs; JNK1, JNK2, and JNK3) promote degenerative processes after neuronal injury and in disease. JNK2 and JNK3 have been shown to promote retinal ganglion cell (RGC) death after optic nerve injury. In their absence, long-term survival of RGC somas is significantly increased after mechanical optic nerve injury. In glaucoma, because optic nerve damage is thought to be a major cause of RGC death, JNKs are an important potential target for therapeutic intervention. To assess the role of JNK2 and JNK3 in an ocular hypertensive model of glaucoma, null alleles of Jnk2 and Jnk3 were backcrossed into the DBA/2J (D2) mouse. JNK activation occurred in RGCs following increased intraocular pressure in D2 mice. However, deficiency of both Jnk2 and Jnk3 together did not lessen optic nerve damage or RGC death. These results differentiate the molecular pathways controlling cell death in ocular hypertensive glaucoma compared with mechanical optic nerve injury. It is further shown that JUN, a pro-death component of the JNK pathway in RGCs, can be activated in glaucoma in the absence of JNK2 and JNK3. This implicates JNK1 in glaucomatous RGC death. Unexpectedly, at younger ages, Jnk2-deficient mice were more likely to develop features of glaucomatous neurodegeneration than D2 mice expressing Jnk2. This appears to be due to a neuroprotective effect of JNK2 and not due to a change in intraocular pressure. The Jnk2-deficient context also unmasked a lesser role for Jnk3 in glaucoma. Jnk2 and Jnk3 double knockout mice had a modestly increased risk of neurodegeneration compared with mice only deficient in Jnk2. Overall, these findings are consistent with pleiotropic effects of JNK isoforms in glaucoma and suggest caution is warranted when using JNK inhibitors to treat chronic neurodegenerative conditions.
Highlights
Glaucoma is a common neurodegenerative disease that causes vision loss, affecting millions of people worldwide[1]
It is demonstrated that activation of JNK2 and JNK3 are not required for glaucomatous degeneration in D2 mice
The importance of JNK signaling in retinal ganglion cell (RGC) death in glaucoma and after optic nerve injury is supported by the increased RGC survival seen in these same two experimental models in Jun-deficient mice[13,15]
Summary
Glaucoma is a common neurodegenerative disease that causes vision loss, affecting millions of people worldwide[1]. Consistent with specific JNK signaling pathway members causing RGC death, disrupting the upstream kinase dual leucine zipper kinase (DLK encoded by Map3k12), or the downstream JNK target JUN, lessens RGC death after mechanical optic nerve injury[13,14,15,16,17,18]. The combined absence of JNK2 and JNK3 prevents JUN activation and RGC death after mechanical optic nerve injury similar to deficiencies in Map3k12 or Jun. It is hypothesized that a similar cell death pathway is activated by axon damage in the lamina that occurs in glaucoma. Jun deficiency has been recently shown to lessen RGC death in D2 mice with glaucoma[15] and other molecules in the JNK signaling pathway are implicated in glaucoma as well[20,21,22]. To better understand the function of JNKs in glaucoma, we tested the function of JNK2 and JNK3 in DBA/2J mice, an ocular hypertensive model of glaucoma[23,24,25,26]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
