Pathogenic TDP-43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock-in mice.

IF 8 1区 医学 Q1 CELL BIOLOGY Aging Cell Pub Date : 2024-08-26 DOI:10.1111/acel.14325
Dazhang Bai, Fuyu Deng, Qingqing Jia, Kaili Ou, Xiang Wang, Junqi Hou, Longhong Zhu, Mingwei Guo, Su Yang, Guohui Jiang, Shihua Li, Xiao-Jiang Li, Peng Yin
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Abstract

Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length-dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre-mRNA, promotes the transport of exon1-intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.

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致病性 TDP-43 可加速亨廷顿氏病基因敲入小鼠中毒性外显子 1 HTT 的生成。
亨廷顿氏病(Huntington's disease,HD)是由编码亨廷蛋白多谷氨酰胺束的 HTT 基因外显子 1 中的 CAG 重复扩增引起的。多聚谷氨酰胺重复扩增的 HTT 外显子 1 片段的形成被认为是 HD 发病的关键步骤。据报道,HTT外显子1的CAG重复长度依赖性异常剪接会导致短的多聚腺苷酸化mRNA被翻译成HTT外显子1蛋白。在正常情况下,TDP-43 主要存在于细胞核中,并在其中调节基因表达。然而,在各种病理情况下,TDP-43 会在细胞质中错误定位。通过研究 HD 基因敲入小鼠,我们探讨了细胞质中的致病性 TDP-43 是否会通过表达无核定位信号的细胞质 TDP-43 而导致 HD 发病。我们发现,HD小鼠脑内的胞浆TDP-43增加,其错误定位会导致运动和步态行为恶化。重要的是,细胞质中的TDP-43通过与小鼠Htt前mRNA的内含子1序列(GU/UG)n结合,促进了外显子1-内含子1 Htt向核糖体的转运,导致外显子1 Htt的异常生成。我们的研究结果表明,细胞质 TDP-43 通过与核未剪接 mRNA 结合并将其转运到核糖体上生成毒性蛋白产物,从而促进 HD 的发病。
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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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