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Artificial Vision 2024

The International Symposium on Visual Prosthetics

05. - 06.12.2024, Aachen, Germany

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The mechanism and targeted therapy of zinc mediating retinal ganglion cell injury through histone H4 deacetylation

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  • Zhe Liu - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou, Guangdong, China
  • J.H. Tang - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou, Guangdong, China
  • Q. Zhang - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou, Guangdong, China
  • L.Y. Liu - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou, Guangdong, China
  • Y.H. Zhuo - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou, Guangdong, China
  • Y.Q. Li - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou, Guangdong, China

Artificial Vision 2024. Aachen, 05.-06.12.2024. Düsseldorf: German Medical Science GMS Publishing House; 2025. Doc24artvis09

doi: 10.3205/24artvis09, urn:nbn:de:0183-24artvis094

Published: May 9, 2025

© 2025 Liu et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Objective: Mammalian optic nerve cannot regenerate once injured. Our previous study found that mobile zinc (Zn2+) increased rapidly after optic nerve injury and it comes from amacrine cell (AC). Whether chelating Zn2+ or specifically knocked out zinc transporter 3 (ZnT3) in ACs significantly promoted axonal regeneration. Three of the four classes of histone deacetylases (HDACs) are Zn2+-dependent, and their inhibitor has Zn2+-binding groups. We aim to explore the role of histone deacetylation and downstream mechanism in Zn2+-mediating RGC injury.

Method: 1. The optic nerve crush (ONC) model was used in this study, AceH4 (acetylated histone4), Tuj1, HDACs, were immunofluorescence stained in the uninjured retina and 1, 3, 5 days after injury;

2. HDAC inhibitor (Scriptaid, VPA), zinc chelator (TPEN), or their combination were injected into the vitreous after ONC. Tuj1 and CTB was used to count RGC and regenerated axons 2 weeks after ONC;

3. AceH4 and Tuj1 were stained before and after injury in wildtype mice with TPEN, ZnT3 systemic knockout mice, or AC-specific knockout ZnT3 mice; HDAC2/3/5 were detected after TPEN treatment.

Result: 1. AceH4 in RGCs decreased significantly after ONC. HDAC2/3/5 transferred from the cytoplasm to the nucleus;

2. Zinc chelators, HDAC inhibitors, and their combination have similar protective effects on RGC survival and regeneration;

3. Treatment with TPEN, global or AC-specific knockout ZnT3 mice restored AceH4 levels in injured RGCs, and TPEN inhibited nuclear import of HDAC2/3/5.

Discussion: AceH4 decreased significantly and HDACs were transferred to the nucleus in RGC at early stage of injury. Zinc chelator acts as HDAC inhibitors to inhibit nuclear import of HDACs. Inhibition of presynaptic Zn2+ releasing by either pharmacological or genetic modification increase AceH4 levels in injured RGCs, promote RGC survival and optic nerve regeneration. This study provides a new and promising therapeutic target for optic nerve regeneration.