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Updated: Mar 29, 2026
Measuring RAN Peptide Toxicity in C. elegans
Published on: April 30, 2020
Uncoupling phototoxicity-elicited neural dysmorphology and death by insidious function and selective impairment of
Kyoung-in Cho1, Victoria Haney1, Dosuk Yoon1
1Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, United States.
Abstract:
Morphological disintegration of neurons is coupled invariably to neural death. In particular, disruption of outer segments of photoreceptor neurons triggers photoreceptor death regardless of the pathological stressors. We show that Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) mice with mutations in SUMO-binding motif (SBM) of cyclophilin-like domain (CLD) of Ran-binding protein 2 (Ranbp2) expressed in a null Ranbp2 background lack untoward effects in photoreceptors in the absence of light-stress. However, compared to wild type photoreceptors, light-stress elicits profound disintegration of outer segments of Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) with paradoxical age-dependent resistance of photoreceptors to death and genotype-independent activation of caspases. Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) exhibit photoreceptor death-independent changes in ubiquitin-proteasome system (UPS), but death-dependent increase of ubiquitin carrier protein 9(ubc9) levels. Hence, insidious functional impairment of SBM of Ranbp2's CLD promotes neuroprotection and uncoupling of photoreceptor degeneration and death against phototoxicity.
Insights
Mutations in Ran-binding protein 2 (Ranbp2) impaired its SUMO-binding motif, leading to photoreceptor degeneration under light stress. Paradoxically, this impairment conferred age-dependent resistance to photoreceptor death.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Neuronal death is linked to morphological disintegration, particularly in photoreceptors where outer segment disruption triggers cell death.
- Ran-binding protein 2 (Ranbp2) plays a role in cellular processes, and its function in photoreceptors is critical for stress response.
Purpose of the Study:
- To investigate the role of the SUMO-binding motif (SBM) within the cyclophilin-like domain (CLD) of Ranbp2 in photoreceptor response to light stress.
- To determine the impact of SBM mutations in Ranbp2 on photoreceptor degeneration and survival.
Main Methods:
- Generation of mutant mice (Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA)) lacking functional Ranbp2 SBM in photoreceptors.
- Exposure of these mice and wild-type controls to light stress.
- Analysis of photoreceptor morphology, death, caspase activation, and ubiquitin-proteasome system (UPS) components.
Main Results:
- Mutant photoreceptors showed outer segment disintegration under light stress but exhibited paradoxical age-dependent resistance to cell death.
- Caspase activation was genotype-independent, while UPS alterations were observed, including a death-dependent increase in ubc9 levels.
- Impaired SBM function in Ranbp2's CLD promoted neuroprotection, uncoupling degeneration from death.
Conclusions:
- Functional impairment of Ranbp2's SBM in the CLD confers neuroprotection against phototoxicity.
- This impairment uncouples photoreceptor degeneration from cell death, suggesting novel mechanisms for neuroprotection in retinal stress responses.
