A G4C2 hexanucleotide repeat expansion in the noncoding region of C9orf72 is the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Putative disease mechanisms underlying c9FTD/ALS include toxicity from sense G4C2 and antisense G2C4 repeat-containing RNA, and from dipeptide repeat (DPR) proteins unconventionally translated from these RNA products. Intracerebroventricular injections with adeno-associated virus (AAV) encoding 2 or 149 G4C2 repeats were performed on postnatal day 0, followed by assessment of behavioral and neuropathological phenotypes. Relative to control mice, gliosis and neurodegeneration accompanied by cognitive and motor deficits were observed in (G4C2)149 mice by 6 months of age. Recapitulating key pathological hallmarks, we also demonstrate that sense and antisense RNA foci, inclusions of poly(GA), poly(GP), poly(GR), poly(PR), and poly(PA) DPR proteins, and inclusions of endogenous phosphorylated TDP-43 (pTDP-43) developed in (G4C2)149 mice but not control (G4C2)2 mice. Notably, proteins that play a role in the regulation of stress granules – RNA-protein assemblies that form in response to translational inhibition and that have been implicated in c9FTD/ALS pathogenesis – were mislocalized in (G4C2)149 mice as early as 3 months of age. Specifically, we observed the abnormal deposition of stress granule components within inclusions immunopositive for poly(GR) and pTDP-43, as well as evidence of nucleocytoplasmic transport defects. Our in vivo model of c9FTD/ALS is the first to robustly recapitulate hallmark features derived from both sense and antisense C9orf72 repeat-associated transcripts complete with neurodegeneration and behavioral impairments. More importantly, the early appearance of persistent pathological stress granules prior to significant pTDP-43 deposition implicates an aberrant stress granule response as a key disease mechanism driving TDP-43 proteinopathy in c9FTD/ALS.

中文翻译：

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与C9orf72相关的TDP-43蛋白病相关的应激颗粒驻留蛋白的异常沉积

在C9orf72的非编码区中的G4C2六核苷酸重复扩增是额颞叶痴呆和肌萎缩性侧索硬化症（c9FTD / ALS）的主要遗传原因。c9FTD / ALS的潜在疾病机制包括来自有义G4C2和反义G2C4重复序列的RNA，以及来自这些RNA产物非常规翻译的二肽重复序列（DPR）蛋白质的毒性。在出生后第0天进行脑室内注射编码2或149个G4C2重复的腺相关病毒（AAV），然后评估行为和神经病理学表型。相对于对照小鼠，到6个月大时，在（G4C2）149小鼠中观察到神经胶质增生和神经变性伴有认知和运动缺陷。概括关键的病理学标志，我们还证明了有义和反义RNA灶，（G4C2）149小鼠中开发的poly（GA），poly（GP），poly（GR），poly（PR）和poly（PA）DPR蛋白的内含物以及内源性磷酸化TDP-43（pTDP-43）的内含物但不包括对照（G4C2）2小鼠。值得注意的是，在应激颗粒调控中起作用的蛋白质-响应翻译抑制而形成的RNA蛋白质组装体，与c9FTD / ALS发病机制有关-早在3个月的（G4C2）149小鼠中就被错误定位。年龄。具体来说，我们观察到了对poly（GR）和pTDP-43呈免疫阳性的内含物中应力颗粒成分的异常沉积，以及核质运输缺陷的证据。我们的c9FTD / ALS体内模型是第一个强有力地概括由有义和反义C9orf72重复相关转录本衍生而来的标志性特征，并伴有神经退行性变和行为障碍的模型。更重要的是，在显着pTDP-43沉积之前早期出现的病理性病理应激颗粒的出现，暗示异常的应激颗粒反应是驱动c9FTD / ALS中TDP-43蛋白病的关键疾病机制。