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Diversity in homeostatic calcium set points predicts retinal ganglion cell survival following optic nerve injury in vivo.

ABSTRACT: Retinal ganglion cell (RGC) degeneration drives vision loss in blinding conditions. RGC death is often triggered by axon degeneration in the optic nerve. Here, we study the contributions of dynamic and homeostatic Ca²⁺ levels to RGC death from axon injury. We find that axonal Ca²⁺ elevations from optic nerve injury do not propagate over distance or reach RGC somas, and acute and chronic Ca²⁺ dynamics do not affect RGC survival. Instead, we discover that baseline Ca²⁺ levels vary widely between RGCs and predict their survival after axon injury, and that lowering these levels reduces RGC survival. Further, we find that well-surviving RGC types have higher baseline Ca²⁺ levels than poorly surviving types. Finally, we observe considerable variation in the baseline Ca²⁺ levels of different RGCs of the same type, which are predictive of within-type differences in survival.

SUBMITTER: McCracken S

PROVIDER: S-EPMC10947246 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Diversity in homeostatic calcium set points predicts retinal ganglion cell survival following optic nerve injury in vivo.

McCracken Sean S Fitzpatrick Michael J MJ Hall Allison L AL Wang Zelun Z Kerschensteiner Daniel D Morgan Josh L JL Williams Philip R PR

Cell reports 20230925 10

Retinal ganglion cell (RGC) degeneration drives vision loss in blinding conditions. RGC death is often triggered by axon degeneration in the optic nerve. Here, we study the contributions of dynamic and homeostatic Ca2+ levels to RGC death from axon injury. We find that axonal Ca2+ elevations from optic nerve injury do not propagate over distance or reach RGC somas, and acute and chronic Ca2+ dynamics do not affect RGC survival. Instead, we discover that baseline ...[more]

PMID: 37751356

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Project description: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.

Dataset Information

Diversity in homeostatic calcium set points predicts retinal ganglion cell survival following optic nerve injury in vivo.

Publications

Diversity in homeostatic calcium set points predicts retinal ganglion cell survival following optic nerve injury in vivo.

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