脊髓和球性肌萎缩少突胶质细胞突触基因表达异常。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Madoka Iida, Kentaro Sahashi, Tomoki Hirunagi, Kenji Sakakibara, Kentaro Maeda, Yohei Iguchi, Jiayi Li, Yosuke Ogura, Masaki Iizuka, Tomohiro Akashi, Kunihiko Hinohara, Shouta Sugio, Hiroaki Wake, Masahiro Nakatochi, Masahisa Katsuno
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引用次数: 0

摘要

脊髓和球性肌萎缩症(SBMA)是一种由雄激素受体(AR)基因CAG重复扩增引起的神经肌肉疾病。为了阐明SBMA中细胞类型特异性的时间基因表达,我们对SBMA小鼠模型(AR-97Q)的脊髓进行了单核RNA测序。在所有细胞类型中,少突胶质细胞在发病前的差异表达基因数量最多。对少突胶质细胞簇的分析表明,与阳离子通道和突触功能相关的通路在疾病发病前被激活,与野生型小鼠相比,AR-97Q小鼠少突胶质细胞向神经元的输出增加。在早期阶段的这些变化在后期阶段被废除了。SBMA少突胶质细胞模型在早期阶段显示出与AR-97Q小鼠相似的表型,例如突触组织的转录变化增加,AR-97Q小鼠少突胶质细胞的Ca2+成像显示Ca2+反应增加。通过对大鼠少突胶质细胞和神经元的共培养,发现少突胶质细胞突变AR影响神经元的活动和同步。这些发现表明,细胞间通讯失调在SBMA早期病理中起着关键作用,突触或离子通道相关蛋白,如接触蛋白相关蛋白2 (Cntnap2)和NALCN通道辅助因子1 (Fam155a),是SBMA的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dysregulated synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. To elucidate the cell type-specific temporal gene expression in SBMA, we performed single-nucleus RNA sequencing on the spinal cords of an SBMA mouse model (AR-97Q). Among all cell types, oligodendrocytes had the highest number of differentially expressed genes before disease onset. Analysis of oligodendrocyte clusters suggested that pathways associated with cation channels and synaptic function were activated before disease onset, with increased output from oligodendrocytes to neurons in AR-97Q mice compared with wild-type mice. These changes in the early stages were abrogated at the advanced stages. An oligodendrocyte model of SBMA showed phenotypes similar to those of AR-97Q mice at early stages, such as increased transcriptional changes in synapse organization, and Ca2+ imaging of oligodendrocytes in AR-97Q mice revealed the increased Ca2+ responses. A coculture system of primary rat oligodendrocytes and neurons revealed that the mutant AR in oligodendrocytes affected the activity and synchronization of neurons. These findings suggest that dysregulated cell-to-cell communication plays a critical role in early SBMA pathology and that synaptic or ion channel-related proteins, such as contactin associated protein 2 (Cntnap2) and NALCN channel auxiliary factor 1 (Fam155a), are potential therapeutic targets for SBMA.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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