Adenovirus-mediated inhibition of proteolytic and cell death pathways in adult rat motoneurons.

蛋白水解机制的损伤已被认为参与ALS运动神经元变性。此外，最近对疾病相关基因（包括TDP-43和FUS）的鉴定开启了ALS研究的新时代。我们制备了编码野生型和突变型TDP-43或FUS的重组腺病毒，以及编码蛋白体（PSMC 1）、内体/ESCRT（VPS 24）和自噬（ATG 5）系统的shRNA的重组腺病毒，以研究运动神经元中的偶联基因转导是否引起ALS病理。编码PSMC 1或ATG 5的shRNA的腺病毒与TDP-43或FUS腺病毒的共感染增强了运动神经元中细胞质聚集体的形成，表明蛋白酶体、内体/ESCRT或自噬系统的损伤加速了ALS中TDP-43和FUS的病理。

Impairment of proteolytic machineries has been recognized to participate in motoneuron degeneration in ALS. Furthermore, recent identifications of disease-associated genes that include TDP-43 and FUS have led to open a new era in ALS research. We produced recombinant adenovirus encoding wild type and mutant TDP-43 or FUS, and those encoding shRNAs for proteosome(PSMC1), endosome/ESCRT(VPS24) and autophagy(ATG5) systems to investigate whether the coupled gene transductions in motoneurons elicit ALS pathology. Co-infections of adenovirus encoding shRNA for PSMC1 or ATG5 with TDP-43 or FUS adenovirus enhanced cytoplasmic aggregate formation in motoneurons, suggesting that impairment of proteasome, endosome/ESCRT, or autophagy system accelerates TDP-43 and FUS pathology in ALS.