Longitudinal and simultaneous profiling of 11 modes of cell death in mouse retina post-optic nerve injury
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Updated: Sep 6, 2025
An Optic Nerve Crush Injury Murine Model to Study Retinal Ganglion Cell Survival
Published on: April 25, 2011
Yao Yao1, Yanxuan Xu2, Jia-Jian Liang2
1Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, Guangdong, China; Shantou University Medical College, Shantou, Guangdong, China.
Abstract:
Retinal ganglion cell (RGC) death is a critical pathological trigger leading to irreversible visual impairment and blindness after optic nerve (ON) injury. Yet, there is still no effective clinical treatment to rescue RGC death after ON injury. Understanding the involvement of different modes of cell death post-ON injury could facilitate the development of targeting treatments against RGC death. Herein we aimed to characterize the regulation of 11 modes of cell death simultaneously and longitudinally in mouse retina post-ON injury. The number of RGCs gradually decreased from Day 3-14 in mice post-ON injury. Increase in the apoptosis (cleaved caspase-3), autolysis (cleaved cathespin B) and pyroptosis (cleaved caspase-1) marker expression in the retina began at Day 3 post-ON injury. Meanwhile, the markers for autophagy (Atg7 and Becn1) and phagocytosis (Mfge8 and Mertk) were downregulated from Day 1 to Day 5. Additionally, the expression of ferroptosis marker (4-hydroxynonenal) was upregulated from Day 7 to Day 14 post-ON injury following the early reduction of Gpx4. Yet, the reduction of parthanatos, sarmoptosis, and mitochondrial permeable transition could be related to autophagy and apoptosis. The markers for necroptosis did not show significant changes post-ON injury. In summary, this study revealed that the activation of apoptosis, autolysis, pyroptosis and ferroptosis, together with the early downregulation of autophagy and phagocytosis, are the major modes of cell death involved in the RGC death post-ON injury. Simultaneously targeting multiple modes of cell death at different time courses could be a potential treatment approach against RGC death for traumatic optic neuropathy.
Insights
Optic nerve injury causes retinal ganglion cell (RGC) death via apoptosis, autolysis, pyroptosis, and ferroptosis. Targeting these cell death pathways offers potential treatments for vision loss.
Area of Science:
- Neuroscience
- Ophthalmology
- Cell Biology
Background:
- Retinal ganglion cell (RGC) death after optic nerve (ON) injury leads to irreversible vision loss.
- Current treatments for ON injury lack efficacy in rescuing RGCs.
- Understanding diverse cell death mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To simultaneously and longitudinally characterize 11 modes of cell death in mouse retina post-ON injury.
- To identify key cell death pathways involved in RGC loss.
- To explore potential therapeutic strategies for traumatic optic neuropathy.
Main Methods:
- Longitudinal analysis of RGC numbers post-ON injury in mice.
- Assessment of markers for apoptosis, autolysis, pyroptosis, autophagy, phagocytosis, ferroptosis, parthanatos, necroptosis, and mitochondrial permeability.
- Quantification of specific protein expression levels related to cell death pathways.
Main Results:
- RGC numbers decreased from Day 3-14 post-ON injury.
- Apoptosis, autolysis, and pyroptosis markers increased starting Day 3.
- Autophagy and phagocytosis markers were downregulated early (Day 1-5).
- Ferroptosis markers increased from Day 7-14, with early Gpx4 reduction.
- Parthanatos, sarmoptosis, and mitochondrial permeability changes correlated with autophagy and apoptosis.
Conclusions:
- Apoptosis, autolysis, pyroptosis, and ferroptosis are major contributors to RGC death post-ON injury.
- Early downregulation of autophagy and phagocytosis exacerbates RGC loss.
- Simultaneously targeting multiple cell death modes offers a promising therapeutic avenue for ON injury.
