BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage

Donahue, RJ; Maes, Margaret E; Grosser, JA; Nickells, RW

BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage

Donahue R, Maes ME, Grosser J, Nickells R. 2020. BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Molecular Neurobiology. 57(2), 1070–1084.

Download (ext.)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035206/ [Submitted Version]

DOI

10.1007/s12035-019-01783-7

Journal Article | Published | English

Scopus indexed

Author

Donahue, RJ; Maes, Margaret E^ISTA ; Grosser, JA; Nickells, RW

Department

Siegert Group

Abstract

Removal of the Bax gene from mice completely protects the somas of retinal ganglion cells (RGCs) from apoptosis following optic nerve injury. This makes BAX a promising therapeutic target to prevent neurodegeneration. In this study, Bax+/− mice were used to test the hypothesis that lowering the quantity of BAX in RGCs would delay apoptosis following optic nerve injury. RGCs were damaged by performing optic nerve crush (ONC) and then immunostaining for phospho-cJUN, and quantitative PCR were used to monitor the status of the BAX activation mechanism in the months following injury. The apoptotic susceptibility of injured cells was directly tested by virally introducing GFP-BAX into Bax−/− RGCs after injury. The competency of quiescent RGCs to reactivate their BAX activation mechanism was tested by intravitreal injection of the JNK pathway agonist, anisomycin. Twenty-four weeks after ONC, Bax+/− mice had significantly less cell loss in their RGC layer than Bax+/+ mice 3 weeks after ONC. Bax+/− and Bax+/+ RGCs exhibited similar patterns of nuclear phospho-cJUN accumulation immediately after ONC, which persisted in Bax+/− RGCs for up to 7 weeks before abating. The transcriptional activation of BAX-activating genes was similar in Bax+/− and Bax+/+ RGCs following ONC. Intriguingly, cells deactivated their BAX activation mechanism between 7 and 12 weeks after crush. Introduction of GFP-BAX into Bax−/− cells at 4 weeks after ONC showed that these cells had a nearly normal capacity to activate this protein, but this capacity was lost 8 weeks after crush. Collectively, these data suggest that 8–12 weeks after crush, damaged cells no longer displayed increased susceptibility to BAX activation relative to their naïve counterparts. In this same timeframe, retinal glial activation and the signaling of the pro-apoptotic JNK pathway also abated. Quiescent RGCs did not show a timely reactivation of their JNK pathway following intravitreal injection with anisomycin. These findings demonstrate that lowering the quantity of BAX in RGCs is neuroprotective after acute injury. Damaged RGCs enter a quiescent state months after injury and are no longer responsive to an apoptotic stimulus. Quiescent RGCs will require rejuvenation to reacquire functionality.

Publishing Year

2020

Date Published

2020-02-01

Journal Title

Molecular Neurobiology

Publisher

Springer Nature

Acknowledgement

This work was supported by National Eye Institute grants R01 EY012223 (RWN), R01 EY030123 (RWN), T32 EY027721 (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), and a Vision Science Core grant P30 EY016665 (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), an unrestricted funding grant from Research to Prevent Blindness (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), the Frederick A. Davis Endowment (RWN), and the Mr. and Mrs. George Taylor Foundation (RWN).

Volume

Issue

Page

1070–1084

ISSN

0893-7648

eISSN

1559-1182

IST-REx-ID

7033

Cite this

Donahue R, Maes ME, Grosser J, Nickells R. BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Molecular Neurobiology. 2020;57(2):1070–1084. doi:10.1007/s12035-019-01783-7

Donahue, R., Maes, M. E., Grosser, J., & Nickells, R. (2020). BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Molecular Neurobiology. Springer Nature. https://doi.org/10.1007/s12035-019-01783-7

Donahue, RJ, Margaret E Maes, JA Grosser, and RW Nickells. “BAX-Depleted Retinal Ganglion Cells Survive and Become Quiescent Following Optic Nerve Damage.” Molecular Neurobiology. Springer Nature, 2020. https://doi.org/10.1007/s12035-019-01783-7.

R. Donahue, M. E. Maes, J. Grosser, and R. Nickells, “BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage,” Molecular Neurobiology, vol. 57, no. 2. Springer Nature, pp. 1070–1084, 2020.

Donahue R, Maes ME, Grosser J, Nickells R. 2020. BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Molecular Neurobiology. 57(2), 1070–1084.

Donahue, RJ, et al. “BAX-Depleted Retinal Ganglion Cells Survive and Become Quiescent Following Optic Nerve Damage.” Molecular Neurobiology, vol. 57, no. 2, Springer Nature, 2020, pp. 1070–1084, doi:10.1007/s12035-019-01783-7.

All files available under the following license(s):

Copyright Statement: