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揭示12型脊髓小脑共济失调发病机制的分子线索

Molecular clues unveiling spinocerebellar ataxia type-12 pathogenesis.

作者信息

Kumar Manish, Sahni Shweta, A Vivekanand, Kumar Deepak, Kushwah Neetu, Goel Divya, Kapoor Himanshi, Srivastava Achal K, Faruq Mohammed

机构信息

Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology (CSIR -IGIB), Mall Road, Delhi 110007, India.

CSIR-HRDC Campus, Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.

出版信息

iScience. 2024 Apr 18;27(5):109768. doi: 10.1016/j.isci.2024.109768. eCollection 2024 May 17.

DOI:10.1016/j.isci.2024.109768
PMID:38711441
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11070597/
Abstract

Spinocerebellar Ataxia type-12 (SCA12) is a neurodegenerative disease caused by tandem CAG repeat expansion in the 5'-UTR/non-coding region of . Molecular pathology of SCA12 has not been studied in the context of CAG repeats, and no appropriate models exist. We found in human SCA12-iPSC-derived neuronal lineage that expanded CAG in transcript forms nuclear RNA foci and were found to sequester variety of proteins. Further, the ectopic expression of transcript containing varying length of CAG repeats exhibits non-canonical repeat-associated non-AUG (RAN) translation in multiple frames in HEK293T cells, which was further validated in patient-derived neural stem cells using specific antibodies. mRNA sequencing of the SCA12 and control neurons have shown a network of crucial transcription factors affecting neural fate, in addition to alteration of various signaling pathways involved in neurodevelopment. Altogether, this study identifies the molecular signatures of SCA12 disorder using patient-derived neuronal cell lines.

摘要

12型脊髓小脑共济失调（SCA12）是一种神经退行性疾病，由[具体基因名称] 5'-UTR/非编码区的串联CAG重复序列扩增引起。尚未在CAG重复序列的背景下研究SCA12的分子病理学，也不存在合适的模型。我们在人SCA12诱导多能干细胞衍生的神经谱系中发现，转录本中扩增的CAG形成核RNA病灶，并发现其隔离多种蛋白质。此外，含有不同长度CAG重复序列的转录本在HEK293T细胞中的异位表达在多个阅读框中表现出非规范的重复相关非AUG（RAN）翻译，这在患者来源的神经干细胞中使用特异性抗体得到了进一步验证。SCA12神经元和对照神经元的mRNA测序显示，除了影响神经发育的各种信号通路发生改变外，还存在一个影响神经命运的关键转录因子网络。总之，本研究使用患者来源的神经元细胞系确定了SCA12疾病的分子特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/ab8a6053e100/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/f379977f9ba9/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/7f70b0768485/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/f186d8a63c01/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/891e92c38c30/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/1eb222279ebc/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/b640924b8b70/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/ab8a6053e100/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/f379977f9ba9/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/7f70b0768485/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/f186d8a63c01/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/891e92c38c30/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/1eb222279ebc/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/b640924b8b70/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea33/11070597/ab8a6053e100/gr6.jpg

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