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ALS/FTD大脑类器官切片培养物显示早期星形细胞和可靶向神经元病理特征
作者:小柯机器人 发布时间:2021/10/24 20:57:50

近日,英国剑桥大学András Lakatos、Gabriel Balmus等研究人员合作发现,人类肌萎缩性侧索硬化症与额颞叶痴呆症(ALS/FTD)大脑类器官切片培养物显示出明显的早期星形细胞和可靶向神经元病理特征。该研究于2021年10月21日在线发表于国际一流学术期刊《自然—神经科学》。

研究人员报告了从人类诱导多能干细胞(iPSC)中获得的大脑类器官切片模型,该模型再现了成熟的皮质结构,并显示了C9ORF72型ALS/FTD的早期分子病理学。利用单细胞RNA测序和生物测定的组合,研究人员揭示了星形胶质细胞和神经元中不同的转录、蛋白稳定和DNA修复障碍。结果表明,星形胶质细胞显示自噬信号蛋白P62的水平增加,深层神经元积累二肽重复蛋白poly(GA)、DNA损伤和发生核分裂,这些都可以通过GSK2606414进行药理救援。因此,患者特异性iPSC衍生的皮质类器官切片培养是一个可重复的转化平台,可以研究临床前ALS/FTD机制以及新的治疗方法。

据介绍,ALS/FTD是一种致命的、目前无法治疗的疾病,其特点是认知能力迅速下降和瘫痪。阐明最初的细胞病理是治疗目标发展的核心,但从无症状的病人身上获取样本并不可行。

附:英文原文

Title: Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology

Author: Szebnyi, Kornlia, Wenger, La M. D., Sun, Yu, Dunn, Alexander W. E., Limegrover, Colleen A., Gibbons, George M., Conci, Elena, Paulsen, Ole, Mierau, Susanna B., Balmus, Gabriel, Lakatos, Andrs

Issue&Volume: 2021-10-21

Abstract: Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we report the development of a cerebral organoid slice model derived from human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical architecture and displays early molecular pathology of C9ORF72 ALS/FTD. Using a combination of single-cell RNA sequencing and biological assays, we reveal distinct transcriptional, proteostasis and DNA repair disturbances in astroglia and neurons. We show that astroglia display increased levels of the autophagy signaling protein P62 and that deep layer neurons accumulate dipeptide repeat protein poly(GA), DNA damage and undergo nuclear pyknosis that could be pharmacologically rescued by GSK2606414. Thus, patient-specific iPSC-derived cortical organoid slice cultures are a reproducible translational platform to investigate preclinical ALS/FTD mechanisms as well as novel therapeutic approaches.

DOI: 10.1038/s41593-021-00923-4

Source: https://www.nature.com/articles/s41593-021-00923-4

期刊信息

Nature Neuroscience:《自然—神经科学》,创刊于1998年。隶属于施普林格·自然出版集团,最新IF:21.126
官方网址:https://www.nature.com/neuro/
投稿链接:https://mts-nn.nature.com/cgi-bin/main.plex