The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding pla...The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.展开更多
目的:探讨针刺对2型糖尿病(T2DM)大鼠肝组织胰岛素受体底物1和2基因(IRS1和2mRNA)表达的影响。方法:给食源性肥胖大鼠腹腔注射小剂量链脲佐菌素(STZ)(25mg/kg)造模成T2DM大鼠,随机分为针刺组、优降糖组和模型组,处理4周后,用快速血糖仪...目的:探讨针刺对2型糖尿病(T2DM)大鼠肝组织胰岛素受体底物1和2基因(IRS1和2mRNA)表达的影响。方法:给食源性肥胖大鼠腹腔注射小剂量链脲佐菌素(STZ)(25mg/kg)造模成T2DM大鼠,随机分为针刺组、优降糖组和模型组,处理4周后,用快速血糖仪检测空腹血糖(FBS)、用放免法检测空腹胰岛素(FINS)、用实时定量荧光PCR(real-tim e RT PCR)法检测肝组织IRS1和2mRNA表达,并与正常组大鼠进行对照。结果:针刺组和优降糖组FBS和FINS比模型组显著降低(P<0.05);模型组IRS1mRNA相对含量是正常组的25%,针刺组为正常组的2.83倍,优降糖组为正常组的1.23倍。模型组IRS2mRNA相对含量为正常组的2.19倍,针刺组IRS2mRNA相对含量为正常组的4.84%,优降糖组IRS2mRNA相对含量为正常组的4.59倍。结论:肝组织IRS1和2mRNA表达异常可能是T2DM的发病机制之一,针刺和优降糖均可上调T2DM大鼠肝组织IRS1mRNA的表达,针刺对T2DM大鼠肝组织IRS1 mRNA表达的上调作用优于优降糖;针刺具有显著抑制T2DM大鼠肝组织IRS2mRNA表达的作用,而优降糖无此作用。展开更多
文摘The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.
文摘目的:探讨针刺对2型糖尿病(T2DM)大鼠肝组织胰岛素受体底物1和2基因(IRS1和2mRNA)表达的影响。方法:给食源性肥胖大鼠腹腔注射小剂量链脲佐菌素(STZ)(25mg/kg)造模成T2DM大鼠,随机分为针刺组、优降糖组和模型组,处理4周后,用快速血糖仪检测空腹血糖(FBS)、用放免法检测空腹胰岛素(FINS)、用实时定量荧光PCR(real-tim e RT PCR)法检测肝组织IRS1和2mRNA表达,并与正常组大鼠进行对照。结果:针刺组和优降糖组FBS和FINS比模型组显著降低(P<0.05);模型组IRS1mRNA相对含量是正常组的25%,针刺组为正常组的2.83倍,优降糖组为正常组的1.23倍。模型组IRS2mRNA相对含量为正常组的2.19倍,针刺组IRS2mRNA相对含量为正常组的4.84%,优降糖组IRS2mRNA相对含量为正常组的4.59倍。结论:肝组织IRS1和2mRNA表达异常可能是T2DM的发病机制之一,针刺和优降糖均可上调T2DM大鼠肝组织IRS1mRNA的表达,针刺对T2DM大鼠肝组织IRS1 mRNA表达的上调作用优于优降糖;针刺具有显著抑制T2DM大鼠肝组织IRS2mRNA表达的作用,而优降糖无此作用。
