Abstract:
Increasing evidence has supported the role of ceramide as a mediator of photoreceptor dysfunction or cell death in ceramide accumulation and deficiency contexts. TLCD3B, a non-canonical ceramide synthase, was previously identified in addition to the six canonical ceramide synthases (CerSs), and the Tlcd3b-/- mouse model exhibited both retinal dysfunction and degeneration. As previous canonical CerS-deficient mouse models failed to display retinal degeneration, the mechanisms of how TLCD3B interacts with CerSs have not been investigated. Additionally, as the ceramide profile of each CerS is distinct, it is unclear whether the overall level or the homeostasis of different ceramide species plays a critical role in photoreceptor degeneration. Interactions between TLCD3B with canonical CerSs expressed in the retina were examined by subretinally injecting recombinant adeno-associated virus 8 vectors containing the Cers2 (rAAV8-CerS2), Cers4 (rAAV8-CerS4) and Cers5 (rAAV8-CerS5) genes. Injection of all three rAAV8-CerS vectors restored retinal functions as indicated by improved electroretinogram responses, but only rAAV8-CerS5 successfully retained retinal morphology in Tlcd3b-/- mice. CerSs and TLCD3B played partially redundant roles. Additionally, rather than acting as an integral entity, different ceramide species had different impacts on retinal cells, suggesting that the maintenance of the overall ceramide profile is critical for retinal function.
摘要:
越来越多的证据支持神经酰胺在神经酰胺积累和缺乏环境中作为光感受器功能障碍或细胞死亡的介质的作用。TLCD3B,一种非经典神经酰胺合成酶,除了六种经典神经酰胺合酶(CerSs)之外,Tlcd3b-/-小鼠模型表现出视网膜功能障碍和变性。由于以前的经典CerS缺陷小鼠模型未能显示视网膜变性,TLCD3B与CerSs相互作用的机制尚未研究.此外,因为每个CerS的神经酰胺谱是不同的,尚不清楚不同神经酰胺种类的总体水平或稳态是否在光感受器变性中起关键作用。通过视网膜下注射含有Cers2(rAAV8-CerS2)的重组腺相关病毒8载体来检查TLCD3B与视网膜中表达的经典CerSs之间的相互作用,Cers4(rAAV8-CerS4)和Cers5(rAAV8-CerS5)基因。所有三种rAAV8-CerS载体的注射均恢复了视网膜功能,如改善的视网膜电图反应所示,但只有rAAV8-CerS5成功保留了Tlcd3b-/-小鼠的视网膜形态。CerSs和TLCD3B扮演部分冗余角色。此外,而不是作为一个完整的实体,不同的神经酰胺对视网膜细胞有不同的影响,提示维持神经酰胺的整体分布对视网膜功能至关重要。