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Jnk2 deficiency increases the rate of glaucomatous neurodegeneration in ocular hypertensive DBA/2J mice.
Cell Death Dis. 2018 06 13; 9(6):705.CD

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.

Authors+Show Affiliations

The Jackson Laboratory, Bar Harbor, ME, 04609, USA.The Jackson Laboratory, Bar Harbor, ME, 04609, USA.Molecular and Cellular Biosciences Department, Rowan University, Glassboro, NJ, 08028, USA.The Jackson Laboratory, Bar Harbor, ME, 04609, USA.Flaum Eye Institute, Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, 14642, USA.The Jackson Laboratory, Bar Harbor, ME, 04609, USA.Flaum Eye Institute, Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, 14642, USA. richard_libby@urmc.rochester.edu.The Jackson Laboratory, Bar Harbor, ME, 04609, USA. simon.john@jax.org. The Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME, 04609, USA. simon.john@jax.org. Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, 02111, USA. simon.john@jax.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29899326

Citation

Harder, Jeffrey M., et al. "Jnk2 Deficiency Increases the Rate of Glaucomatous Neurodegeneration in Ocular Hypertensive DBA/2J Mice." Cell Death & Disease, vol. 9, no. 6, 2018, p. 705.
Harder JM, Williams PA, Soto I, et al. Jnk2 deficiency increases the rate of glaucomatous neurodegeneration in ocular hypertensive DBA/2J mice. Cell Death Dis. 2018;9(6):705.
Harder, J. M., Williams, P. A., Soto, I., Foxworth, N. E., Fernandes, K. A., Freeburg, N. F., Libby, R. T., & John, S. W. M. (2018). Jnk2 deficiency increases the rate of glaucomatous neurodegeneration in ocular hypertensive DBA/2J mice. Cell Death & Disease, 9(6), 705. https://doi.org/10.1038/s41419-018-0705-8
Harder JM, et al. Jnk2 Deficiency Increases the Rate of Glaucomatous Neurodegeneration in Ocular Hypertensive DBA/2J Mice. Cell Death Dis. 2018 06 13;9(6):705. PubMed PMID: 29899326.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Jnk2 deficiency increases the rate of glaucomatous neurodegeneration in ocular hypertensive DBA/2J mice. AU - Harder,Jeffrey M, AU - Williams,Pete A, AU - Soto,Ileana, AU - Foxworth,Nicole E, AU - Fernandes,Kimberly A, AU - Freeburg,Nelson F, AU - Libby,Richard T, AU - John,Simon W M, Y1 - 2018/06/13/ PY - 2017/09/25/received PY - 2018/04/20/accepted PY - 2018/03/12/revised PY - 2018/6/15/entrez PY - 2018/6/15/pubmed PY - 2019/11/7/medline SP - 705 EP - 705 JF - Cell death & disease JO - Cell Death Dis VL - 9 IS - 6 N2 - 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. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/29899326/Jnk2_deficiency_increases_the_rate_of_glaucomatous_neurodegeneration_in_ocular_hypertensive_DBA/2J_mice_ L2 - https://doi.org/10.1038/s41419-018-0705-8 DB - PRIME DP - Unbound Medicine ER -