Inherited Retinal Degeneration: Towards the Development of a Combination Therapy Targeting Histone Deacetylase, Poly (ADP-Ribose) Polymerase, and Calpain
Inherited retinal degeneration (IRD) represents a diverse group of gene mutation-induced blinding diseases. In IRD, the loss of photoreceptors is often connected to excessive activation of histone-deacetylase (HDAC), poly-ADP-ribose-polymerase (PARP), and calpain-type proteases (calpain). Moreover, the inhibition of either HDACs, PARPs, or calpains has previously shown promise in preventing photoreceptor cell death, although the relationship between these enzyme groups remains unclear. To explore this further, organotypic retinal explant cultures derived from wild-type mice and rd1 mice as a model for IRD were treated with different combinations of inhibitors specific for HDAC, PARP, and calpain. The outcomes were assessed using in situ activity assays for HDAC, PARP, and calpain, immunostaining for activated calpain-2, and the TUNEL assay for cell death detection. We confirmed that inhibition of either HDAC, PARP, or calpain reduced rd1 mouse photoreceptor degeneration, with the HDAC inhibitor Vorinostat (SAHA) being most effective. Calpain activity was reduced by inhibition of both HDAC and PARP whereas PARP activity was only reduced by HDAC inhibition. Unexpectedly, combined treatment with either PARP and calpain inhibitors or HDAC and calpain inhibitors did not produce synergistic rescue of photoreceptors. Together, these results indicate that in rd1 photoreceptors, HDAC, PARP, and calpain are part of the same degenerative pathway and are activated in a sequence that begins with HDAC and ends with calpain.
基金:
Tistou and Charlotte Kerstan Foundation; Zinke Heritage Foundation; National Natural Science Foundation of China [82260213, 81960180]; Medical Leading Talents Training Program of Yunnan Provincial Health Commission [L-2019029]; Yunnan Provincial Department of Science and Technology [202001AY070001-165]; Kunming Medical University on Applied Basic Research [202001AY070001-165]
第一作者机构:[1]Yunnan Univ, Affiliated Hosp, Yunnan Eye Inst, Key Lab Yunnan Prov, 176 Qingnian, Kunming 650021, Peoples R China[2]Kunming Med Univ, 1168 Chunrongxi Rd, Kunming 650500, Peoples R China
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推荐引用方式(GB/T 7714):
Dong Yujie,Yan Jie,Yang Ming,et al.Inherited Retinal Degeneration: Towards the Development of a Combination Therapy Targeting Histone Deacetylase, Poly (ADP-Ribose) Polymerase, and Calpain[J].BIOMOLECULES.2023,13(4):doi:10.3390/biom13040581.
APA:
Dong, Yujie,Yan, Jie,Yang, Ming,Xu, Wenrong,Hu, Zhulin...&Jiao, Kangwei.(2023).Inherited Retinal Degeneration: Towards the Development of a Combination Therapy Targeting Histone Deacetylase, Poly (ADP-Ribose) Polymerase, and Calpain.BIOMOLECULES,13,(4)
MLA:
Dong, Yujie,et al."Inherited Retinal Degeneration: Towards the Development of a Combination Therapy Targeting Histone Deacetylase, Poly (ADP-Ribose) Polymerase, and Calpain".BIOMOLECULES 13..4(2023)