Jefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
Sci Rep. 2022 Apr 4;12(1):5644. doi: 10.1038/s41598-022-09593-z.
Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress.
与 C9orf72 肌萎缩侧索硬化症和额颞叶痴呆（ALS/FTD）相关的六核苷酸 G4C2 扩展产生了五种不同的二肽重复蛋白（DPR）物种，这些物种可能具有毒性。关于单一 DPR 对疾病发病机制的贡献，我们还有很多需要了解。我们在这里表明，短重复长度足以使 DPR 聚-GR 在体外产生神经毒性，这是以前未观察到的现象。在我们的新型基因敲入小鼠模型中也观察到了这种毒性，该模型的特征是短聚-GR 在中枢神经系统（CNS）中广泛表达。我们在这些小鼠中观察到了性别特异性的慢性 ALS/FTD 样表型，包括轻微的运动神经元丧失，但没有 TDP-43 定位错误，以及运动和认知障碍。我们认为该模型可以作为通过二次打击形式的应激来增强表型的基础。
