Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase
Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase
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DOI：
10.1038/nm1784
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发表时间：
2008-07-01
期刊：
影响因子：
82.9
通讯作者：
Wahlestedt, Claes
中科院分区：
文献类型：
--
作者：
Faghihi, Mohammad Ali;Modarresi, Farzaneh;Wahlestedt, Claes
最近的研究表明，许多编码蛋白质的信使RNA都有天然的反义转录伙伴，其中大多数似乎是非编码RNA。在这里，我们确定了一个保守的非编码反义转录本的β-分泌酶-1(BACE1)，一个关键的酶在阿尔茨海默病的病理生理学。BACE1反义转录本(BACE1-AS)在体外和体内调节BACE1mRNA和BACE1蛋白的表达。当暴露于包括淀粉样β1-42(Aβ1-42)在内的各种细胞应激源时，BACE1-AS的表达增加，增加了BACE1 mRNA的稳定性，并通过转录后前馈机制产生额外的Aβ1-42。在阿尔茨海默病受试者和淀粉样前体蛋白转基因小鼠中，BACE1-AS浓度升高。这些数据表明，BACE1 mRNA的表达受调控的非编码RNA的控制，该RNA可能推动阿尔茨海默病相关的病理生理学。综上所述，我们报告了一个长的非编码RNA与阿尔茨海默病中Aβ1-42丰度的增加直接相关。
Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for beta-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 (A beta 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional A beta 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of A beta 1-42 in Alzheimer's disease.