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

BACE is an enzyme necessary for the generation of neurotoxic amyloid-β in Alzheimer's disease. Claes Wahlestedt and his colleagues identify a noncoding RNA that is upregulated in the brains of individuals with Alzheimer's disase. This noncoding RNA increases expression of BACE, driving amy...

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Vydané v:	Nature medicine Ročník 14; číslo 7; s. 723 - 730
Hlavní autori:	Faghihi, Mohammad Ali, Modarresi, Farzaneh, Khalil, Ahmad M, Wood, Douglas E, Sahagan, Barbara G, Morgan, Todd E, Finch, Caleb E, St. Laurent III, Georges, Kenny, Paul J, Wahlestedt, Claes
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.07.2008 Nature Publishing Group
Predmet:	Aged Aged, 80 and over Alzheimer Disease - enzymology Alzheimer Disease - etiology Alzheimer Disease - metabolism Alzheimer Disease - physiopathology Alzheimer's disease Amyloid beta-Peptides - metabolism Amyloid beta-protein Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals Antisense RNA Aspartic Acid Endopeptidases - genetics Aspartic Acid Endopeptidases - metabolism Biomedical and Life Sciences Biomedicine Cancer Research Cell Line, Tumor Development and progression Feedback, Physiological Gene expression Gene Expression Regulation Genetic aspects Health aspects Humans Infectious Diseases Male Metabolic Diseases Mice Mice, Transgenic Middle Aged Models, Genetic Molecular Medicine Neuroblastoma - pathology Neurosciences Peptide Fragments - metabolism Physiological aspects Protein Processing, Post-Translational RNA, Messenger - metabolism RNA, Small Interfering - pharmacology RNA, Untranslated - analysis RNA, Untranslated - metabolism Transcription, Genetic Transfection United States
ISSN:	1078-8956, 1546-170X, 1546-170X
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Shrnutí:	BACE is an enzyme necessary for the generation of neurotoxic amyloid-β in Alzheimer's disease. Claes Wahlestedt and his colleagues identify a noncoding RNA that is upregulated in the brains of individuals with Alzheimer's disase. This noncoding RNA increases expression of BACE, driving amyloid-β generation and possibly disease progression. 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 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 . 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 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 Aβ 1–42 in Alzheimer's disease.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/nm1784