Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma.
Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma.
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DOI：
10.1186/s13024-016-0091-6
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发表时间：
2016-04-06
影响因子：
15.1
通讯作者：
Howell GR
中科院分区：
文献类型：
--
作者：
Williams PA;Tribble JR;Pepper KW;Cross SD;Morgan BP;Morgan JE;John SW;Howell GR
青光眼是一种复杂的多因素疾病，其特征在于视网膜神经节细胞及其轴突的丧失，导致视觉功能下降。青光眼中视网膜神经节细胞损伤的最早期事件目前尚不清楚。视网膜神经节细胞死亡似乎是区室化的，索马、树突和轴突的变化可能通过不同的机制发生。有越来越多的证据表明，其他神经退行性疾病的神经元树突经历了一个长期的萎缩，包括修剪突触，细胞损失之前。此外，最近的证据表明补体级联在青光眼和其他疾病中的突触修剪中的作用。使用遗传（DBA/2 J小鼠）和诱导型（大鼠微珠）青光眼模型，我们首先证明了在轴突或索马丧失之前的时间点存在视网膜神经节细胞突触和树突的丧失。我们接下来确定补体成分1（C1）在青光眼早期突触丢失和树突萎缩中的作用。使用基因敲除C1 qa（D2.C1qa-/-小鼠）或药理学抑制C1（在大鼠珠模型），我们表明，抑制C1足以保护树突和突触结构。这项研究进一步支持评估补体调节疗法预防青光眼视网膜神经节细胞变性的潜力。
Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases. Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa-/- mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture. This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma.