Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase.
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 (Abeta 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Abeta 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 Abeta 1-42 in Alzheimer's disease.
Faghihi
Mohammad Ali
MA
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
Modarresi
Farzaneh
F
Khalil
Ahmad M
AM
Wood
Douglas E
DE
Sahagan
Barbara G
BG
Morgan
Todd E
TE
Finch
Caleb E
CE
St Laurent
Georges
G
Kenny
Paul J
PJ
Wahlestedt
Claes
C
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008957:Models, Genetic; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D022661:RNA, Untranslated / Q000032:analysis / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse