Villa-Vasquez Suly S, Nazlamova Liliya, Pengelly Reuben J, Wilson David I, Baralle Diana, Wheway Gabrielle
School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
BMC Mol Cell Biol. 2025 Sep 9;26(1):27. doi: 10.1186/s12860-025-00551-x.
Retinitis pigmentosa (RP) affects around 1 in 4000 individuals and represents approximately 25% of cases of vision loss in adults, through death of retinal rod and cone photoreceptor cells. It remains a largely untreatable disease, and research is needed to identify potential targets for therapy. Mutations in 94 different genes have been identified as causing RP, including AGBL5 which encodes the main deglutamylase that regulates and maintains functional levels of cilia tubulin glutamylation, which is essential to initiate ciliogenesis, maintain cilia stability and motility. In this study we use CRISPR-mutated AGBL5 clonal retinal pigmented epithelial cell lines to characterise the cilia defects and hyperglutamylation in these cells and identify potential targets for treatment. We demonstrate rescue of glutamylation to wild-type levels and restoration of ciliogenesis in AGBL5 mutant cells through exogenous expression of AGBL5, and independently through both stable genomic mutation and transient siRNA knockdown of TTLL5, which encodes a tubulin glutamylase. This identifies two potential routes to treatment for patients with RP associated with mutations in AGBL5 which will need to be explored further in retinal organoid models of this disease.
视网膜色素变性（RP）影响约四千分之一的人，约占成人视力丧失病例的25%，是由视网膜视杆和视锥光感受器细胞死亡所致。它在很大程度上仍是一种无法治愈的疾病，需要开展研究以确定潜在的治疗靶点。已确定94种不同基因的突变可导致RP，其中包括AGBL5，该基因编码主要的去谷氨酰胺酶，可调节并维持纤毛微管蛋白谷氨酰化的功能水平，而这对于启动纤毛发生、维持纤毛稳定性和运动性至关重要。在本研究中，我们使用CRISPR突变的AGBL5克隆视网膜色素上皮细胞系来表征这些细胞中的纤毛缺陷和过度谷氨酰化，并确定潜在的治疗靶点。我们通过AGBL5的外源性表达，以及独立地通过稳定基因组突变和对编码微管蛋白谷氨酰胺酶的TTLL5进行瞬时siRNA敲低，证明了AGBL5突变细胞中的谷氨酰化恢复到野生型水平以及纤毛发生的恢复。这确定了两条针对与AGBL5突变相关的RP患者的潜在治疗途径，这需要在该疾病的视网膜类器官模型中进一步探索。
