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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 <jats:italic>Jnk2<\/jats:italic> and <jats:italic>Jnk3<\/jats:italic> were backcrossed into the DBA\/2J (D2) mouse. JNK activation occurred in RGCs following increased intraocular pressure in D2 mice. However, deficiency of both <jats:italic>Jnk2<\/jats:italic> and <jats:italic>Jnk3<\/jats:italic> 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, <jats:italic>Jnk2<\/jats:italic>-deficient mice were more likely to develop features of glaucomatous neurodegeneration than D2 mice expressing <jats:italic>Jnk2<\/jats:italic>. This appears to be\u00a0due to a neuroprotective effect of JNK2 and not due to a change in intraocular pressure. The <jats:italic>Jnk2-<\/jats:italic>deficient context also unmasked a lesser role for <jats:italic>Jnk3<\/jats:italic> in glaucoma. <jats:italic>Jnk2<\/jats:italic> and <jats:italic>Jnk3<\/jats:italic> double knockout mice had a modestly increased risk of neurodegeneration compared with mice only deficient in <jats:italic>Jnk2<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1038\/s41419-018-0705-8","type":"journal-article","created":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T09:35:05Z","timestamp":1528882505000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Jnk2 deficiency increases the rate of glaucomatous neurodegeneration in ocular hypertensive DBA\/2J mice"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3832-3553","authenticated-orcid":false,"given":"Jeffrey M.","family":"Harder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6194-8397","authenticated-orcid":false,"given":"Pete A.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana","family":"Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole E.","family":"Foxworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly A.","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson F.","family":"Freeburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard T.","family":"Libby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon. 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