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DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice.
Cell Death Discov. 2019; 5:140.CD

Abstract

Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been implicated as drivers of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 after glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas, but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration.

Authors+Show Affiliations

1Department of Ophthalmology, Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY USA. 2Cell Biology of Disease Graduate Program, University of Rochester Medical Center, Rochester, NY USA. 3The Center for Visual Sciences, University of Rochester, Rochester, NY USA.1Department of Ophthalmology, Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY USA. 4Medical Scientist Training Program, University of Rochester Medical Center, Rochester, NY USA.1Department of Ophthalmology, Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY USA. 3The Center for Visual Sciences, University of Rochester, Rochester, NY USA. 5Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31632741

Citation

Marola, Olivia J., et al. "DDIT3 (CHOP) Contributes to Retinal Ganglion Cell Somal Loss but Not Axonal Degeneration in DBA/2J Mice." Cell Death Discovery, vol. 5, 2019, p. 140.
Marola OJ, Syc-Mazurek SB, Libby RT. DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice. Cell Death Discov. 2019;5:140.
Marola, O. J., Syc-Mazurek, S. B., & Libby, R. T. (2019). DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice. Cell Death Discovery, 5, 140. https://doi.org/10.1038/s41420-019-0220-4
Marola OJ, Syc-Mazurek SB, Libby RT. DDIT3 (CHOP) Contributes to Retinal Ganglion Cell Somal Loss but Not Axonal Degeneration in DBA/2J Mice. Cell Death Discov. 2019;5:140. PubMed PMID: 31632741.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice. AU - Marola,Olivia J, AU - Syc-Mazurek,Stephanie B, AU - Libby,Richard T, Y1 - 2019/10/10/ PY - 2019/08/04/received PY - 2019/09/04/accepted PY - 2019/10/22/entrez PY - 2019/10/22/pubmed PY - 2019/10/22/medline KW - Cell death in the nervous system KW - Glaucoma SP - 140 EP - 140 JF - Cell death discovery JO - Cell Death Discov VL - 5 N2 - Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been implicated as drivers of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 after glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas, but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration. SN - 2058-7716 UR - https://www.unboundmedicine.com/medline/citation/31632741/DDIT3__CHOP__contributes_to_retinal_ganglion_cell_somal_loss_but_not_axonal_degeneration_in_DBA/2J_mice_ L2 - https://doi.org/10.1038/s41420-019-0220-4 DB - PRIME DP - Unbound Medicine ER -
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