RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2024-08-31 DOI:10.1002/ana.27068

David J. Burrows PhD, Alexander McGown PhD, Olfat Abduljabbar PhD, Lydia M. Castelli PhD, Pamela J. Shaw MBBS, MD, Guillaume M. Hautbergue PhD, Tennore M. Ramesh DVM, PhD

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Abstract

Objective

Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.

Methods

A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.

Results

Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.

Interpretation

The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058–1069

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斑马鱼中与 C9orf72 相关的二肽重复蛋白的 RAN 翻译再现了肌萎缩侧索硬化症的特征，并确定了低温疗法作为一种治疗策略。

目的：C9orf72基因的六核苷酸重复扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）最常见的遗传病因。大量证据表明，二肽重复（DPRs）蛋白是细胞和动物模型中神经元损伤的主要驱动因素之一：方法：建立了一个纯重复相关非 AUG（RAN）翻译的 C9orf72-ALS/FTD 斑马鱼模型。对胚胎和成年转基因斑马鱼裂解物进行了调查，以确定是否存在 RAN 翻译的 DPR 物种和成年发病的运动障碍。利用 C9orf72 细胞模型以及胚胎 C9orf72-ALS/FTD 斑马鱼，探索了低体温治疗温度管理 (TTM) 作为 C9orf72-ALS/FTD 的潜在治疗方案：在这里，我们描述了一种纯 RAN 翻译的 C9orf72-ALS/FTD 斑马鱼模型，该模型表现出明显的 RAN 翻译 DPR 病理学和进行性运动衰退。我们进一步证明，在 C9orf72-ALS/FTD 细胞模型以及 C9orf72-ALS/FTD 胚胎斑马鱼中，低温-TTM 可导致 DPR 种类的显著减少：本文详述的转基因模型为进一步研究RAN-翻译在C9orf72-ALS/FTD中的作用以及进一步了解神经保护策略的机制提供了一种中等通量的体内研究工具。低温-TTM为探索C9orf72-ALS/FTD提供了一条可行的治疗途径。ann neurol 2024.

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.