Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy
Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy
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DOI：
10.1186/s13024-019-0310-z
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发表时间：
2019-02-15
影响因子：
15.1
通讯作者：
Petrucelli, Leonard
中科院分区：
文献类型：
--
作者：
Chew, Jeannie;Cook, Casey;Petrucelli, Leonard
研究背景C9 orf 72非编码区G（4）C（2）六核苷酸重复序列扩增是额颞叶痴呆和肌萎缩侧索硬化（c9 FTD/ALS）的主要遗传病因。c9 FTD/ALS潜在的假定疾病机制包括含正义G（4）C（2）和反义G（2）C（4）重复序列的RNA以及从这些RNA产物非常规翻译的二肽重复序列（DPR）蛋白的毒性。方法在出生后0 d侧脑室分别注射编码2个或149个G（4）C（2）重复序列的腺相关病毒（AAV），观察6月龄（G（4）C（2））（149）小鼠的行为学和神经病理学表型。概括关键的病理学特征，我们还证明了正义和反义RNA病灶，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）的内含物在（G（4）C（2））（149）小鼠中形成，但在对照（G（4）C（2））（2）小鼠中没有。值得注意的是，早在3月龄的（G（4）C（2））（149）小鼠中，在应激颗粒调节中发挥作用的蛋白质--响应于翻译抑制形成的RNA-蛋白质组装体，并与c9 FTD/ALS发病机制有关--被错误定位。具体而言，我们观察到的异常沉积的压力颗粒组件内的夹杂物免疫阳性的聚（GR）和pTDP-43，以及核质运输deficiency.ConclusionsOur的证据c9 FTD/ALS的体内模型是第一个强大的recapitulate标志性功能来自正义和反义C9 orf 72重复相关的转录完成与神经变性和行为障碍。更重要的是，在显著pTDP-43沉积之前早期出现持续性病理性应激颗粒暗示异常应激颗粒反应是驱动c9 FTD/ALS中TDP-43蛋白质病的关键疾病机制。
BackgroundA G(4)C(2) 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 G(4)C(2) and antisense G(2)C(4) repeat-containing RNA, and from dipeptide repeat (DPR) proteins unconventionally translated from these RNA products. MethodsIntracerebroventricular injections with adeno-associated virus (AAV) encoding 2 or 149 G(4)C(2) repeats were performed on postnatal day 0, followed by assessment of behavioral and neuropathological phenotypes.ResultsRelative to control mice, gliosis and neurodegeneration accompanied by cognitive and motor deficits were observed in (G(4)C(2))(149) mice by 6months 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 (G(4)C(2))(149) mice but not control (G(4)C(2))(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 (G(4)C(2))(149) mice as early as 3months 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.ConclusionsOur 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.