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首页> 外文期刊>Neuropathology: official journal of the Japanese Society of Neuropathology >Adenoviral expression of TDP-43 and FUS genes and shRNAs for protein degradation pathways in rodent motoneurons in vitro and in vivo
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Adenoviral expression of TDP-43 and FUS genes and shRNAs for protein degradation pathways in rodent motoneurons in vitro and in vivo

机译：TDP-43和FUS基因和shRNA的腺病毒表达在体外和体内在啮齿动物运动神经元中的蛋白降解途径

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摘要

Formation of cytoplasmic aggregates in neuronal and glial cells is one of the pathological hallmarks of amyotrophic lateral sclerosis (ALS). Mutations in two genes encoding transactivation response (TAR) DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS), both of which are main constituents of cytoplasmic aggregates, have been identified in patients with familial and sporadic ALS. Impairment of protein degradation machineries has also been recognized to participate in motoneuron degeneration in ALS. In the present study, we produced recombinant adenovirus vectors encoding wild type and mutant TDP-43 and FUS, and those encoding short hairpin RNAs (shRNAs) for proteasome (PSMC1), autophagy (ATG5), and endosome (VPS24) systems to investigate whether the coupled gene transductions in motoneurons by these adenoviruses elicit ALS pathology. Cultured neurons, astrocytes and oligodendrocytes differentiated from adult rat neural stem cells and motoneurons derived from mouse embryonic stem cells were successfully infected with these adenoviruses showing cytoplasmic aggregate formation. When these adenoviruses were injected into the facial nerves of adult rats, exogenous TDP-43 and FUS proteins were strongly expressed in facial motoneurons by a retrograde axonal transport of the adenoviruses. Co-infections of adenovirus encoding shRNA for PSMC1, ATG5 or VPS24 with TDP-43 or FUS adenovirus enhanced cytoplasmic aggregate formation in facial motoneurons, suggesting that impairment of protein degradation pathways accelerates formation of TDP-43 and FUS-positive aggregates in ALS.
机译：神经元和神经胶质细胞中细胞质聚集体的形成是肌萎缩性侧索硬化症（ALS）的病理标志之一。在家族性和散发性ALS患者中，已经鉴定出两种编码反式激活应答（TAR）DNA结合蛋白43（TDP-43）和融合在肉瘤（FUS）中的基因的突变，这两种都是细胞质聚集体的主要成分。还已经认识到蛋白质降解机制的损伤参与了ALS中的运动神经元变性。在本研究中，我们生产了编码野生型和突变型TDP-43和FUS的重组腺病毒载体，以及编码用于蛋白酶体（PSMC1），自噬（ATG5）和内体（VPS24）系统的短发夹RNA（shRNA）的重组腺病毒载体，以研究是否这些腺病毒在运动神经元中进行的耦合基因转导引发了ALS病理。从成年大鼠神经干细胞和源自小鼠胚胎干细胞的运动神经元中分化出来的培养神经元，星形胶质细胞和少突胶质细胞已成功地被这些腺病毒感染，这些腺病毒显示出细胞质聚集体的形成。当将这些腺病毒注射到成年大鼠的面神经中时，通过腺病毒的逆轴突运输，外源TDP-43和FUS蛋白在面部运动神经元中强烈表达。编码PSMC1，ATG5或VPS24的shRNA的腺病毒与TDP-43或FUS腺病毒的共感染增强了面部运动神经元的细胞质聚集体形成，这表明蛋白降解途径的损伤加速了ALS中TDP-43和FUS阳性聚集体的形成。

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