Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-04-19 DOI:10.1007/s00401-024-02720-2
Evan Udine, Mariely DeJesus-Hernandez, Shulan Tian, Sofia Pereira das Neves, Richard Crook, NiCole A. Finch, Matthew C. Baker, Cyril Pottier, Neill R. Graff-Radford, Bradley F. Boeve, Ronald C. Petersen, David S. Knopman, Keith A. Josephs, Björn Oskarsson, Sandro Da Mesquita, Leonard Petrucelli, Tania F. Gendron, Dennis W. Dickson, Rosa Rademakers, Marka van Blitterswijk
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Abstract

The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.

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C9orf72重复扩增患者小脑中的大量转录组改变
肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)最主要的遗传病因是基因 C9orf72 的重复扩增。重要的是,C9orf72重复扩增的转录组学后果在很大程度上仍不清楚。在这里,我们使用短线程 RNA 测序(RNAseq)分析了小脑转录组,检测了 C9orf72 重复扩增患者的转录组变化。我们将研究重点放在了小脑上,因为在这一神经解剖区域,与 C9orf72 相关的关键病变非常多,而 TDP-43 病变和神经元丢失却很少。与之前的研究结果一致,我们发现在将C9orf72基因扩增的患者与没有C9orf72重复扩增的患者和对照组进行比较时,C9orf72基因的表达量减少,而同源染色体基因的表达量增加。有趣的是,我们发现了 1000 多个替代剪接事件,其中包括 4 个以前与 ALS 和/或 FTLD 相关的基因。我们还发现,与无 C9orf72 重复扩增的患者和对照组相比,C9orf72 患者的隐性剪接增加了。此外,我们还证明,选择性 RNA 结合蛋白的表达水平与隐性剪接接头的包含有关。总之,本研究探讨了 C9orf72 患者死后组织中的小脑(一个不受严重神经变性影响的区域)是否存在广泛的转录组变化。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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