A synthetic PGC1α co-activator reprograms microglial immunometabolism to preserve cone function in retinal degeneration
- 1Department of Ophthalmology, Columbia University, New York, NY, United States
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, PGC1 induction suppressed LPS-driven interferon signaling and cytokine release, yet Seahorse analysis and isotopologue tracing showed that energy metabolism remained altered. We therefore fused PGC1 to a multivalent p65-HSF1 module, yielding ~2.5-fold higher nuclear receptor output than native PGC1 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 PGC1 co-activators provide a means to sustain oxidative metabolism under inflammatory pressure.
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BibTeX
@misc{winogrodzki2026synthetic,
title = {{A synthetic PGC1α co-activator reprograms microglial immunometabolism to preserve cone function in retinal degeneration}},
author = {T. Winogrodzki and J. Hernandez-Reyes and R. Solanky and R. Lowery and G. Komissarov and W. Huang and B. Wang and N. Makrides and S. Davis and S. Liu and Y.-S. Li and W.-H. Wu and N. Nolan and R. van de Werken and A. Demirkol and A. Knudsen and N. Surawatsatien and Y. Li and J. Hurley and S. H. Tsang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.753881},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.753881v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A synthetic PGC1α co-activator reprograms microglial immunometabolism to preserve cone function in retinal degeneration
AU - T. Winogrodzki
AU - J. Hernandez-Reyes
AU - R. Solanky
AU - R. Lowery
AU - G. Komissarov
AU - W. Huang
AU - B. Wang
AU - N. Makrides
AU - S. Davis
AU - S. Liu
AU - Y.-S. Li
AU - W.-H. Wu
AU - N. Nolan
AU - R. van de Werken
AU - A. Demirkol
AU - A. Knudsen
AU - N. Surawatsatien
AU - Y. Li
AU - J. Hurley
AU - S. H. Tsang
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.753881
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.753881v1
AB - 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, PGC1 induction suppressed LPS-driven interferon signaling and cytokine release, yet Seahorse analysis and isotopologue tracing showed that energy metabolism remained altered. We therefore fused PGC1 to a multivalent p65-HSF1 module, yielding ~2.5-fold higher nuclear receptor output than native PGC1 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 PGC1 co-activators provide a means to sustain oxidative metabolism under inflammatory pressure.
ER -