在婴儿神经细胞类脂膜脂质沉着病小鼠模型中,Akap5 将突触功能障碍与神经炎症信号传导联系起来

IF 2.8 4区 医学 Q2 NEUROSCIENCES
Kevin P. Koster, Zach Fyke, T. T. Nguyen, Amanda Niqula, Lorena Y. Noriega-González, Kevin M. Woolfrey, M. Dell’Acqua, S. Cologna, Akira Yoshii
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引用次数: 0

摘要

棕榈酰化和去棕榈酰化是一种易变的翻译后脂质修饰调节蛋白质运输和降解的二分过程。去棕榈酰化酶--棕榈酰蛋白硫代酯酶 1(PPT1)与破坏性小儿神经退行性疾病--婴儿神经细胞类脂膜脂质沉着病(CLN1)有关。CLN1的特征是神经元中自发荧光的溶酶体储存物质(AFSM)的积累和强烈的神经炎症。越来越多的证据表明,除了细胞废物堆积外,CLN1 的症状还与突触过程的破坏有关。事实上,在一种被称为突触缩放的突触可塑性过程中,大脑皮层神经元中 Ppt1 功能的缺失会导致 GluA1 AMPA 受体(AMPAR)亚基的突触结合失调。然而,导致这种畸变的机制尚不清楚。在这里,我们利用 Ppt1-/- 小鼠模型(雌雄均可)来进一步研究 Ppt1 如何调节突触可塑性以及其中断如何影响下游信号通路。为此,我们进行了棕榈酰蛋白组筛选,结果发现 Akap5 在 Ppt1-/- 突触中过度棕榈酰化。扩展我们之前的数据,在体内诱导由 Akap5 调节的突触缩放会导致 Ppt1-/- 小鼠体内 GluA1 的过度上调。这种突触变化与疾病病理加剧有关。此外,Akap5和炎症相关的转录调节因子--活化T细胞核因子(NFAT)在Ppt1-/-皮层神经元中变得敏感。用 FDA 批准的治疗药物 FK506(他克莫司)抑制 NFAT 激活的上游调节因子钙神经蛋白,可适度改善 Ppt1-/- 小鼠的神经炎症。这些研究结果表明,去棕榈酰化的缺失会抑制突触蛋白的贩运,并通过与 Akap5 相关的机制导致神经炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Akap5 links synaptic dysfunction to neuroinflammatory signaling in a mouse model of infantile neuronal ceroid lipofuscinosis
Palmitoylation and depalmitoylation represent dichotomic processes by which a labile posttranslational lipid modification regulates protein trafficking and degradation. The depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), is associated with the devastating pediatric neurodegenerative condition, infantile neuronal ceroid lipofuscinosis (CLN1). CLN1 is characterized by the accumulation of autofluorescent lysosomal storage material (AFSM) in neurons and robust neuroinflammation. Converging lines of evidence suggest that in addition to cellular waste accumulation, the symptomology of CLN1 corresponds with disruption of synaptic processes. Indeed, loss of Ppt1 function in cortical neurons dysregulates the synaptic incorporation of the GluA1 AMPA receptor (AMPAR) subunit during a type of synaptic plasticity called synaptic scaling. However, the mechanisms causing this aberration are unknown. Here, we used the Ppt1−/− mouse model (both sexes) to further investigate how Ppt1 regulates synaptic plasticity and how its disruption affects downstream signaling pathways. To this end, we performed a palmitoyl-proteomic screen, which provoked the discovery that Akap5 is excessively palmitoylated at Ppt1−/− synapses. Extending our previous data, in vivo induction of synaptic scaling, which is regulated by Akap5, caused an excessive upregulation of GluA1 in Ppt1−/− mice. This synaptic change was associated with exacerbated disease pathology. Furthermore, the Akap5- and inflammation-associated transcriptional regulator, nuclear factor of activated T cells (NFAT), was sensitized in Ppt1−/− cortical neurons. Suppressing the upstream regulator of NFAT activation, calcineurin, with the FDA-approved therapeutic FK506 (Tacrolimus) modestly improved neuroinflammation in Ppt1−/− mice. These findings indicate that the absence of depalmitoylation stifles synaptic protein trafficking and contributes to neuroinflammation via an Akap5-associated mechanism.
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来源期刊
CiteScore
7.10
自引率
2.70%
发文量
74
审稿时长
14 weeks
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