A synthetic PGC1α co-activator reprograms microglial immunometabolism to preserve cone function in retinal degeneration
Year: 2026
Type: preprint
Abstract: Retinitis pigmentosa (RP) is genetically heterogeneous, yet initiating mutations converge on primary rod degeneration followed by cone dysfunction and loss. Activated microglia are implicated in this secondary phase, but whether selective immunometabolic reprogramming of microglia preserves retinal function remains unknown. In human iPSC-derived microglia and retinal CD11b⁺ cells, PGC1α induction suppressed LPS-driven interferon signaling and cytokine release, yet Seahorse analysis and isotopologue tracing showed that energy metabolism remained altered. We therefore fused PGC1α to a multivalent p65-HSF1 module, yielding ~2.5-fold higher nuclear receptor output than native PGC1α and coordinated engagement of oxidative and anti-inflammatory programs in mouse retinal CD11b⁺ cells. Microglia-restricted expression in humanized RHOP347L mice preserved photopic responses through six months, increased retinal thickness and promoted ramified subretinal IBA1⁺ morphology. Microglial immunometabolism thus represents a potentially genotype-independent neuroprotective target in RP, and engineered PGC1α co-activators provide a means to sustain oxidative metabolism under inflammatory pressure.
Authors: Thomas Winogrodzki, Jayvin Hernandez-Reyes, Rajvir Solanky, Richard Lowery, Georgy Komissarov, Wen Huang, Boyuan Wang, Neoklis Makrides, Sharifa Davis, Siyuan Liu, Yong-Shi Li, Wen-Hsuan Wu, Nicholas Nolan, Robert van de Werken, Aykut Demirkol, Anders Knudsen, Nuntachai Surawatsatien, Yao Li, James Hurley, Stephen H Tsang
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G161103358, G2349931395, G3099082787, G3119513115, Core Facilities for Vision Research, G4072863281, G4494920243, G5996497050, Identification of the specific risk allele responsible for oxidative stress in ARMS2/HTRA1-related AMD, G6902378652, Therapeutic gene editing and multimodal imaging in juvenile macular degeneration , G7198951180, G7472006007, Translational Gene Therapy for CNGB1 Retinitis Pigmentosa, G8110661541, Precision genome surgery in autologous stem cell transplant, Defining Barriers to Gene Therapy, Enhancing cone survival in retinitis pigmentosa through cell-specific therapeutic CRISPR editing of a roxadustat target, Gene Editing and Silencing in Phototransduction, Cancer Center Support Grant
OpenAlex ID: W7220470776