The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.
Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, Qinghai, China.
BMC Biol. 2024 Jun 10;22(1):134. doi: 10.1186/s12915-024-01932-y.
Inherited retinal dystrophies (IRDs) are a group of debilitating visual disorders characterized by the progressive degeneration of photoreceptors, which ultimately lead to blindness. Among the causes of this condition, mutations in the PCYT1A gene, which encodes the rate-limiting enzyme responsible for phosphatidylcholine (PC) de novo synthesis via the Kennedy pathway, have been identified. However, the precise mechanisms underlying the association between PCYT1A mutations and IRDs remain unclear. To address this knowledge gap, we focused on elucidating the functions of PCYT1A in the retina.
We found that PCYT1A is highly expressed in Müller glial (MG) cells in the inner nuclear layer (INL) of the retina. Subsequently, we generated a retina-specific knockout mouse model in which the Pcyt1a gene was targeted (Pcyt1a-RKO or RKO mice) to investigate the molecular mechanisms underlying IRDs caused by PCYT1A mutations. Our findings revealed that the deletion of Pcyt1a resulted in retinal degenerative phenotypes, including reduced scotopic electroretinogram (ERG) responses and progressive degeneration of photoreceptor cells, accompanied by loss of cells in the INL. Furthermore, through proteomic and bioinformatic analyses, we identified dysregulated retinal fatty acid metabolism and activation of the ferroptosis signalling pathway in RKO mice. Importantly, we found that PCYT1A deficiency did not lead to an overall reduction in PC synthesis within the retina. Instead, this deficiency appeared to disrupt free fatty acid metabolism and ultimately trigger ferroptosis.
This study reveals a novel mechanism by which mutations in PCYT1A contribute to the development of IRDs, shedding light on the interplay between fatty acid metabolism and retinal degenerative diseases, and provides new insights into the treatment of IRDs.
遗传性视网膜营养不良（IRDs）是一组严重的视觉障碍疾病，其特征是感光器逐渐退化，最终导致失明。在导致这种疾病的原因中，已经鉴定出编码从头合成磷脂酰胆碱（PC）的限速酶的 PCYT1A 基因突变。然而，PCYT1A 突变与 IRDs 之间关联的确切机制仍不清楚。为了解决这一知识空白，我们专注于阐明 PCYT1A 在视网膜中的功能。
我们发现 PCYT1A 在视网膜内核层（INL）的 Müller 胶质细胞（MG）中高度表达。随后，我们生成了一种视网膜特异性敲除小鼠模型，其中靶向 Pcyt1a 基因（Pcyt1a-RKO 或 RKO 小鼠），以研究由 PCYT1A 突变引起的 IRDs 的分子机制。我们的研究结果表明，Pcyt1a 的缺失导致视网膜退行性表型，包括暗视视网膜电图（ERG）反应减弱和感光器细胞进行性退化，同时 INL 中的细胞丢失。此外，通过蛋白质组学和生物信息学分析，我们发现 RKO 小鼠中视网膜脂肪酸代谢失调和铁死亡信号通路激活。重要的是，我们发现 PCYT1A 缺乏并没有导致视网膜内 PC 合成的整体减少。相反，这种缺乏似乎破坏了游离脂肪酸代谢，最终引发铁死亡。
本研究揭示了 PCYT1A 突变导致 IRDs 发展的新机制，阐明了脂肪酸代谢与视网膜退行性疾病之间的相互作用，并为 IRDs 的治疗提供了新的思路。
