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Compartmentalized citrullination in Muller glial endfeet during retinal degeneration
Sarah I Palko1, Nicholas J Saba1, Elias Mullane1
1Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030.
Abstract:
Muller glia (MG) play a central role in reactive gliosis, a stress response associated with rare and common retinal degenerative diseases, including age-related macular degeneration (AMD). The posttranslational modification citrullination targeting glial fibrillary acidic protein (GFAP) in MG was initially discovered in a panocular chemical injury model. Here, we report in the paradigms of retinal laser injury, a genetic model of spontaneous retinal degeneration (JR5558 mice) and human wet-AMD tissues that MG citrullination is broadly conserved. After laser injury, GFAP polymers that accumulate in reactive MG are citrullinated in MG endfeet and glial cell processes. The enzyme responsible for citrullination, peptidyl arginine deiminase-4 (PAD4), localizes to endfeet and associates with GFAP polymers. Glial cell-specific PAD4 deficiency attenuates retinal hypercitrullination in injured retinas, indicating PAD4 requirement for MG citrullination. In retinas of 1-mo-old JR5558 mice, hypercitrullinated GFAP and PAD4 accumulate in MG endfeet/cell processes in a lesion-specific manner. Finally, we show that human donor maculae from patients with wet-AMD also feature the canonical endfeet localization of hypercitrullinated GFAP. Thus, we propose that endfeet are a "citrullination bunker" that initiates and sustains citrullination in retinal degeneration.
Insights
Muller glia (MG) citrullination of GFAP is conserved in retinal degeneration models and human AMD. This process, mediated by PAD4 in MG endfeet, may initiate and sustain retinal damage.
Area of Science:
- Neuroscience
- Ophthalmology
- Cell Biology
Background:
- Muller glia (MG) are crucial in reactive gliosis, a response to retinal degenerative diseases like age-related macular degeneration (AMD).
- Citrullination, a posttranslational modification of glial fibrillary acidic protein (GFAP) in MG, was previously observed in chemical injury models.
Purpose of the Study:
- To investigate the conservation and mechanisms of MG citrullination in various retinal degeneration paradigms.
- To identify the enzyme responsible for GFAP citrullination and its role in retinal injury and disease.
Main Methods:
- Utilized laser injury models, a genetic mouse model (JR5558), and human wet-AMD macular tissues.
- Investigated GFAP citrullination and peptidyl arginine deiminase-4 (PAD4) localization in retinal tissues.
- Assessed the impact of glial cell-specific PAD4 deficiency on retinal hypercitrullination.
Main Results:
- MG citrullination of GFAP is broadly conserved across laser injury, genetic degeneration models, and human wet-AMD.
- Peptidyl arginine deiminase-4 (PAD4) localizes to MG endfeet and associates with GFAP polymers.
- Glial cell-specific PAD4 deficiency significantly reduces retinal hypercitrullination in injured retinas.
Conclusions:
- Muller glia endfeet act as a "citrullination bunker," initiating and sustaining GFAP citrullination in retinal degeneration.
- PAD4 is essential for MG citrullination in response to retinal injury.
- Hypercitrullinated GFAP in MG endfeet is a conserved hallmark of retinal degeneration, including human AMD.
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