Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice
Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice
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DOI：
10.1093/brain/awx272
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发表时间：
2017-12-01
期刊：
影响因子：
14.5
通讯作者：
van Zundert, Brigitte
中科院分区：
文献类型：
--
作者：
Bustos, Fernando J.;Ampuero, Estibaliz;van Zundert, Brigitte
Dlg4编码突触后受体聚集蛋白PSD95，在衰老和阿尔茨海默病中表达减少。Bustos等人。设计一种锌指蛋白，通过改变其表观遗传状态来改变Dlg4的表达，并使用该结构来修复老年和阿尔茨海默病小鼠的记忆缺陷。Dlg4基因编码突触后密度蛋白95(PSD95)，这是一种主要的突触蛋白，聚集在谷氨酸受体上，对可塑性至关重要。PSD95水平在衰老和神经退行性疾病中降低，包括阿尔茨海默病和亨廷顿病。DYS调控Dlg4/PSD95或其他可塑性基因转录的表观遗传学机制在很大程度上是未知的，这限制了靶向表观基因组治疗的发展。我们分析了Dlg4/PSD95在海马组织中的表观遗传格局，并设计了一种Dlg4/PSD95基因打靶策略：设计一个Dlg4/PSD95锌指DNA结合域并融合到效应域上，以抑制(G9a，Suvdel76，Skd)或激活(VP64)转录，产生人工转录因子或表观遗传编辑(甲基化H3K9)。这些表观编辑改变了关键的组蛋白标记，随后改变了Dlg4/PSD95的表达，这对几个海马神经元的可塑性过程产生了重要影响。有趣的是，转导人工转录因子PSD95-VP64可以挽救老年和阿尔茨海默病小鼠的记忆缺陷。总而言之，这项工作证实了PSD95是记忆中的关键角色，并确立了表观遗传编辑作为治疗人类神经疾病的潜在疗法。
Expression of Dlg4, which encodes the postsynaptic receptor clustering protein PSD95, is decreased in ageing and Alzheimer's disease. Bustos et al. engineer a zinc finger protein that modifies Dlg4 expression by changing its epigenetic state, and use the construct to rescue memory deficits in aged and Alzheimer's disease mice.The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer's disease and Huntington's disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer's disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders.