Abstract:
Circular RNA (circRNA) molecules have critical functions during brain development and in brain-related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6), stemming from the Huntington\'s disease (HD) gene locus that is most abundant in the central nervous system (CNS). We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD model systems. The mouse orthologue, circHtt(2,3,4,5,6), is expressed during embryogenesis, increases during nervous system development, and is aberrantly upregulated in the presence of the expanded CAG tract. While an IRES-like motif was predicted in circH TT (2,3,4,5,6), the circRNA does not appear to be translated in adult mouse brain tissue. Nonetheless, a modest, but consistent fraction of circHtt(2,3,4,5,6) associates with the 40S ribosomal subunit, suggesting a possible role in the regulation of protein translation. Finally, circHtt(2,3,4,5,6) overexpression experiments in HD-relevant STHdh striatal cells revealed its ability to modulate CAG expansion-driven cellular defects in cell-to-substrate adhesion, thus uncovering an unconventional modifier of HD pathology.
摘要:
环状RNA(circularRNA)分子在大脑发育和大脑相关疾病中具有关键功能。这里,我们鉴定并验证了一个circRNA,大约(2,3,4,5,6),源于中枢神经系统(CNS)中最丰富的亨廷顿氏病(HD)基因座。我们发现了它在不同哺乳动物物种中的进化保守性,以及人类和小鼠HD模型系统中HTT外显子1中circHTT(2,3,4,5,6)水平与CAG重复序列长度之间的相关性。老鼠直系同源,circirHtt(2,3,4,5,6),在胚胎发生过程中表达,在神经系统发育过程中增加,并且在扩张的CAG束存在下异常上调。虽然在大约TT(2,3,4,5,6)中预测了类似IRES的图案,circRNA在成年小鼠脑组织中似乎没有翻译。尽管如此,一个谦虚的,但是circHtt(2,3,4,5,6)的一致分数与40S核糖体亚基相关,提示可能在蛋白质翻译的调节中发挥作用。最后,在HD相关的STHdh纹状体细胞中进行的circHtt(2,3,4,5,6)过表达实验揭示了其在细胞与底物粘附中调节CAG扩增驱动的细胞缺陷的能力,从而揭示了HD病理学的非常规修饰。