与发育和癫痫性脑病相关的 CACNA2D2 双重突变会影响α2δ-2 的钙通道依赖性和突触功能。

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Neurochemistry Pub Date : 2024-08-19 DOI:10.1111/jnc.16197
Sabrin Haddad, Cornelia Ablinger, Ruslan Stanika, Manuel Hessenberger, Marta Campiglio, Nadine J Ortner, Petronel Tuluc, Gerald J Obermair
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引用次数: 0

摘要

α2δ蛋白是电压门控钙通道的辅助亚基,调节通道膜的表达和电流特性。除了通道功能外,α2δ 蛋白还能调节突触的形成、分化和突触接线。考虑到这些重要功能,CACNA2D1-4(α2δ-1 至 -4异构体的编码基因)与神经系统、神经发育和神经精神疾病有关就不足为奇了。CACNA2D2 基因突变与发育性癫痫性脑病(DEE)和小脑萎缩有关。在本研究中,我们对α2δ-2中的p.R593P突变进行了详细的功能表征,这一同源突变先前在两个患有DEE的兄弟姐妹中被发现。重要的是,我们分析了α2δ-2的钙通道依赖功能和突触功能。我们的数据显示,小鼠α2δ-2中相应的p.R596P突变大大降低了α2δ-2的膜表达和突触靶向性。这种缺陷与突触后 CaV1.3 通道生物物理特性的改变有关,但在 tsA201 细胞中异源表达时对突触前 CaV2.1 通道没有影响。然而,α2δ-2_R596P 在海马神经元原代培养物中的同源表达会影响 α2δ-2诱导内源性 CaV2.1 通道突触前丰度和突触前钙离子瞬态显著增加的能力。此外,我们的数据表明,除了降低膜表达外,p.R596P 突变还减少了谷氨酸能突触中 GABAA 受体的跨突触招募和突触前突触素聚集。最后,α2δ-2_R596P 会降低转导海马神经元中谷氨酸能微型突触后电流的振幅。总之,我们的数据将人类双倍p.R593P突变与潜在的严重神经发育障碍紧密地联系在一起,并强调了研究α2δ突变不仅在通道病变中而且在突触病变中的重要性。
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A biallelic mutation in CACNA2D2 associated with developmental and epileptic encephalopathy affects calcium channel-dependent as well as synaptic functions of α2δ-2.

α2δ proteins serve as auxiliary subunits of voltage-gated calcium channels and regulate channel membrane expression and current properties. Besides their channel function, α2δ proteins regulate synapse formation, differentiation, and synaptic wiring. Considering these important functions, it is not surprising that CACNA2D1-4, the genes encoding for α2δ-1 to -4 isoforms, have been implicated in neurological, neurodevelopmental, and neuropsychiatric disorders. Mutations in CACNA2D2 have been associated with developmental and epileptic encephalopathy (DEE) and cerebellar atrophy. In our present study, we performed a detailed functional characterization of the p.R593P mutation in α2δ-2, a homozygous mutation previously identified in two siblings with DEE. Importantly, we analyzed both calcium channel-dependent as well as synaptic functions of α2δ-2. Our data show that the corresponding p.R596P mutation in mouse α2δ-2 drastically decreases membrane expression and synaptic targeting of α2δ-2. This defect correlates with altered biophysical properties of postsynaptic CaV1.3 channel but has no effect on presynaptic CaV2.1 channels upon heterologous expression in tsA201 cells. However, homologous expression of α2δ-2_R596P in primary cultures of hippocampal neurons affects the ability of α2δ-2 to induce a statistically significant increase in the presynaptic abundance of endogenous CaV2.1 channels and presynaptic calcium transients. Moreover, our data demonstrate that in addition to lowering membrane expression, the p.R596P mutation reduces the trans-synaptic recruitment of GABAA receptors and presynaptic synapsin clustering in glutamatergic synapses. Lastly, the α2δ-2_R596P reduces the amplitudes of glutamatergic miniature postsynaptic currents in transduced hippocampal neurons. Taken together, our data strongly link the human biallelic p.R593P mutation to the underlying severe neurodevelopmental disorder and highlight the importance of studying α2δ mutations not only in the context of channelopathies but also synaptopathies.

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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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