Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase

Abstract

Recent transcriptomics 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 β-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. It seems that the argument for concordant regulation can only be made in the experiments with the siRNA against BACE1-AS. This convention has been followed throughout the manuscript. Please check carefully.]. Upon exposure to various cell stressors including amyloid-β 1-42 (Aβ 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Aβ 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease as well as 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 Aβ 1-42 in Alzheimer's disease.Sequential cleavage of amyloid precursor protein (APP) by BACE1, the β-site cleaving enzyme essential for Aβ 1-42 and amyloid-β 1-40 (Aβ 1-40) biosynthesis 1 , and γ-secretase NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptinitiates the 'amyloid cascade' that is central to Alzheimer's disease pathophysiology2 , 3. Oligomers of Aβ 1-42 produced by BACE1 influence key aspects of Alzheimer's disease4 -9 . Studies have revealed elevated brain BACE1 concentrations in subjects with Alzheimer's disease compared with normal controls [10][11][12][13][14][15] . However, controversy exists concerning the extent of BACE1 upregulation and whether this upregulation involves BACE1 mRNA or protein [16][17][18] .Loss of BACE1 results in numerous behavioral and physiological deficits, including memory loss 19 , emotional deficits 20 , myelination defects in peripheral nerves 21,22 and loss of synaptic plasticity 20 . Thus, the subtle but crucial boundaries between BACE1 physiology and pathology indicate that BACE1 expression must be tightly regulated, allowing the enzyme to perform its physiological functions while avoiding the serious consequences of over-or underexpression.Here we report that BACE1-AS, a natural antisense transcript, plays a part in determining BACE1 expression. BACE1-AS rapidly and reversibly upregulates BACE1 levels in response to a variety of stresses, including Aβ 1-42 exposure. Furthermore, we show elevated BACE1-AS in several brain regions of individuals with Alzheimer's disease. These data suggest that this previously unexamined noncoding RNA has a role in regulating BACE1 and in driving Alzheimer's disease pathology. RESULTS Identification of BACE1 natural antisense transcriptBACE1...

Long noncoding RNA are aberrantly expressed in vivo in the cystic fibrosis bronchial epithelium

“…They can act as decoys by binding to RNA or protein and titrating these away from other molecules; they can act as guides to direct localisation of ribonucleoprotein complexes; and they can act as scaffolds and structural platforms for nuclear processes. Aberrant expression of lncRNAs have been associated with various human conditions, including those as diverse as cancers (Yu et al, 2012), myocardial infarction (Ishii et al, 2006a) and Alzheimer"s disease (Faghihi et al, 2008). lncRNAs have been…”

Bidirectional regulation between WDR83 and its natural antisense transcript DHPS in gastric cancer

“…To investigate whether the overlapping 3′UTR of WDR83 and DHPS RNA duplex affected the stability of the mRNA, we blocked any new mRNA synthesis with α-amanitin (an RNA polymerase II inhibitor) and analyzed the expression of WDR83, DHPS, GAPDH and 18S RNA over a 24-h period. 18S RNA, which was a product of RNA polymerase I and was unchanged after α-amanitin treatment, served as the internal control [9]. As shown in Figure 5C, compared with control siRNAs, treatment with the specific siRNAs against DHPS resulted in a decreased stability of WDR83 mRNA; WDR83 knockdown also caused a reduced stability of DHPS mRNA.…”

“…It was reported that the RNA-RNA duplex could protect mRNA from RNase degradation and enhance mRNA stability [9,20]. To investigate whether the overlapping 3′UTR of WDR83 and DHPS RNA duplex affected the stability of the mRNA, we blocked any new mRNA synthesis with α-amanitin (an RNA polymerase II inhibitor) and analyzed the expression of WDR83, DHPS, GAPDH and 18S RNA over a 24-h period.…”

“…However, few reports have investigated whether bidirectional regulation can exist between antisense RNAs and sense protein-coding genes. In addition, recent efforts have paid close attention to noncoding RNAs (ncRNAs) as antisense transcripts of sense genes [8,9]. To date, no systematic studies have been published, which discuss antisense protein-coding genes that can affect sense protein-coding genes.…”

ADAR-mediated RNA editing in non-coding RNA sequences

“…However, there are only a few cases showing that editing can influence miRNA or siRNA biogenesis and target recognition, and the function of edited lncRNAs is still unclear. Moreover, non-coding RNAs are associated with cancer [13][14][15], Prader-Willi syndrome [16,17], autism [18,19], and Alzheimer's disease [20], but no evidence shows that edited non-coding RNAs are related to human disease. ADARs are highly expressed in brain tissue, thus edited non-coding RNAs most likely play a regulatory role in brain development, functional diversification, and neurological disease.…”