Trifunović Dragana, Arango-Gonzalez Blanca, Comitato Antonella, Barth Melanie, Del Amo Eva M, Kulkarni Manoj, Sahaboglu Ayse, Hauck Stefanie M, Urtti Arto, Arsenijevic Yvan, Ueffing Marius, Marigo Valeria, Paquet-Durand François
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Hum Mol Genet. 2016 Oct 15;25(20):4462-4472. doi: 10.1093/hmg/ddw275.
Cone photoreceptor cell death as it occurs in certain hereditary retinal diseases is devastating, with the affected patients suffering from a loss of accurate and colour vision. Regrettably, these hereditary cone diseases are still untreatable to date. Thus, the identification of substances able to block or restrain cone cell death is of primary importance. We studied the neuroprotective effects of a histone deacetylase inhibitor, Trichostatin A (TSA), in a mouse model of inherited, primary cone degeneration (cpfl1). We show that HDAC inhibition protects cpfl1 cones in vitro, in retinal explant cultures. More importantly, in vivo, a single intravitreal TSA injection significantly increased cone survival for up to 16 days post-injection. In addition, the abnormal, incomplete cone migration pattern in the cpfl1 retina was significantly improved by HDAC inhibition. These findings suggest a crucial role for HDAC activity in primary cone degeneration and highlight a new avenue for future therapy developments for cone dystrophies and retinal diseases associated with impaired cone migration.
在某些遗传性视网膜疾病中发生的视锥光感受器细胞死亡是毁灭性的，受影响的患者会丧失精确的彩色视觉。遗憾的是，这些遗传性视锥疾病至今仍无法治疗。因此，鉴定能够阻断或抑制视锥细胞死亡的物质至关重要。我们在遗传性原发性视锥变性（cpfl1）小鼠模型中研究了组蛋白去乙酰化酶抑制剂曲古抑菌素A（TSA）的神经保护作用。我们发现，在视网膜外植体培养中，HDAC抑制在体外可保护cpfl1视锥细胞。更重要的是，在体内，单次玻璃体内注射TSA可使注射后长达16天的视锥细胞存活率显著提高。此外，HDAC抑制可显著改善cpfl1视网膜中异常、不完全的视锥细胞迁移模式。这些发现表明HDAC活性在原发性视锥变性中起关键作用，并为未来视锥营养不良和与视锥细胞迁移受损相关的视网膜疾病的治疗发展开辟了一条新途径。
