Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (10): 5044-5050.doi: 10.4103/NRR.NRR-D-24-01102

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Poly(ADP-ribose) polymerase regulates transient receptor potential channel M2-dependent calpain activation in rd1 mouse retinal degeneration

Jie Yan1, 2, #, Lei Kong1, #, Zhijian Zhao3, Qianlu Yang4, Lan Wang2, Qianxi Yang4, Christian Harteneck5, †, Kangwei Jiao1, Zhulin Hu1, François Paquet-Durand2, *   

  1. 1Yunnan Eye Institute & Key Laboratory of Yunnan Province, Yunnan Eye Disease Clinical Medical Center, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, Yunnan Province, China; 
    2Cell Death Mechanism Group, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany; 
    3High-resolution Functional Imaging and Test Group, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany; 
    4The Third Affiliated Hospital of Kunming Medical University &Yunnan Cancer Hospital, Kunming, Yunnan Province, China; 
    5Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany
  • Online:2026-10-15 Published:2026-06-15
  • Contact: François Paquet-Durand, PhD, francois.paquet-durand@uni-tuebingen.de.
  • Supported by:
    This study was supported by the Medical Leading Talents Training Program of Yunnan Provincial Health Commission, No. L-2019029 (to ZH); the Yunnan Provincial Health Commission Clinical Medicine Center Research Project, Nos. 2024YNLCYXZX0326,  2024YNLCYXZX0339 (both to JY); the Yunnan Fundamental Research Kunming Medical University Projects, No. 202501AY070001-217 (to JY); the Yunnan University Medical Research Foundation, No. YDYXJJ2025-0056 (to JY); Key Project of Yunnan Fundamental Research Projects, No. 202301AS070046 (to KJ); the Charlotte and Tistou Kerstan Foundation (to FPD); and the Zinke Heritage Foundation (to FPD).

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Abstract: Inherited retinal degeneration refers to untreatable blinding diseases characterized by progressive photoreceptor loss. Photoreceptor degeneration is often associated with an excessive activation of poly(ADP-ribose) polymerase and Ca2+-dependent calpain-type proteases. To explore the interplay between poly(ADP-ribose) polymerase and calpain activity, we employed organotypic retinal explant cultures derived from wild-type mice and from the rd1 mouse model for inherited retinal degeneration. Retinae were treated with the poly(ADP-ribose) polymerase inhibitors INO1001 or Olaparib, the poly(ADP-ribose) glycohydrolase inhibitor JA2131, or the transient receptor potential channel M2 blocker 8-Br-ADPR. Readouts included the terminal deoxynucleotidyl transferase dUTP nick end labeling assay to detect cell death, in situ activity assays for histone-deacetylases, poly(ADP-ribose) polymerase, and calpain, as well as immunostaining for activated calpain-2, and poly(ADP-ribose). Poly(ADP-ribose) polymerase, poly(ADP-ribose) glycohydrolase, and transient receptor potential channel M2 inhibition reduced calpain activity and calpain-2 activation. Poly(ADP-ribose) polymerase activity was decreased by poly(ADP-ribose) polymerase and transient receptor potential channel M2 inhibitors but not by poly(ADP-ribose) glycohydrolase inhibition. Remarkably, the poly(ADP-ribose) polymerase inhibitor INO1001 increased histone-deacetylase activity unlike any of the other compounds. When combined with the poly(ADP-ribose) glycohydrolase inhibitor JA2131, INO1001 reduced photoreceptor cell death in a synergistic fashion, although such synergy was not observed for calpain or poly(ADP-ribose) polymerase activity. Moreover, synergistic photoreceptor preservation was not observed when JA2131 was combined with the poly(ADP-ribose) polymerase inhibitor Olaparib. Overall, these results indicate that in rd1 photoreceptors, poly(ADP-ribose) polymerase controls calpain activity via poly(ADP-ribose) glycohydrolase and transient receptor potential channel M2-induced Ca2+ influx. We also characterized INO1001 as potentially more beneficial for inherited retinal degeneration treatment than Olaparib. Our study details the complexity of poly(ADP-ribose) polymerase-signaling in photoreceptors and identifies poly(ADP-ribose) glycohydrolase and transient receptor potential channel M2 as new targets for inherited retinal degeneration therapy development.

Key words: Ca2+, calcium channels, cyclic-guanosine-monophosphate (cGMP), PARthanatos, poly(ADP-ribose) polymerase-2 (PARP-2), retinitis pigmentosa