A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs effect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profile. Furthermore, we show co-expression of specific DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD.

中文翻译：

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C9orf72 相关二肽重复超过 1000 个重复单元的共表达揭示了果蝇中年龄和组合特异性的表型特征。


C9orf72（C9orf72-SMCR8 复合亚基）基因座内的大内含子六核苷酸重复扩增 (GGGGCC) 是额颞叶痴呆 (FTD) 和运动神经元疾病 (MND) 最常见的遗传原因。在患者中，这种扩展的长度通常为数百至数千个重复单元。重复相关的非 AUG 扩增翻译会导致有毒、病理性二肽重复蛋白 (DPR) 的形成。迄今为止，仍然缺乏表达重复长度超过数百个重复的 C9orf72 相关 DPR 的体内模型。因此，我们对生理相关重复长度 DPR 如何影响老化体内系统中的神经系统的理解仍然有限。在这项研究中，我们生成了表达长度超过 1000 个重复单位的 DPR 的果蝇模型，这是人类已知的病理长度。使用这些模型，我们证明每个 DPR 都表现出独特的、年龄依赖性的表型和病理特征。此外，我们发现特定 DPR 组合的共表达会导致独特的、年龄依赖性的表型，而这是通过单个 DPR 的表达观察不到的。我们认为这些模型代表了一种独特的体内工具，用于剖析疾病病理学中涉及的分子机制，为 MND 和 FTD 的研究开辟了新途径。