Expression of the Alzheimer protease BACE1 is suppressed via its 5'-untranslated region.
The aspartyl protease BACE1 has a pivotal role in the pathogenesis of Alzheimer's disease. Recently, it was shown that in Alzheimer's disease patients, BACE1 levels were elevated although mRNA levels were not changed compared with controls. Here, we demonstrate that the 5'-untranslated region (5'UTR) of BACE1 controls the rate of BACE1 translation. In the presence of the 5'UTR, we observed more than 90% reduction of BACE1 protein levels in HEK293, COS7 and H4 cells, and a similar reduction of BACE1 activity in vitro. mRNA levels were not affected, demonstrating that the 5'UTR repressed the translation but not the transcription of BACE1. The 3'UTR did not affect BACE1 expression. An extensive mutagenesis analysis predicts that the GC-rich region of the 5'UTR forms a constitutive translation barrier, which may prevent the ribosome from efficiently translating the BACE1 mRNA. Our data therefore demonstrate translational repression as a new mechanism controlling BACE1 expression.
Lammich
Sven
S
Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany.
Schöbel
Susanne
S
Zimmer
Ann-Katrin
AK
Lichtenthaler
Stefan F
SF
Haass
Christian
C
D020121:5' Untranslated Regions / Q000235:genetics*; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D001483:Base Sequence; D015536:Down-Regulation; D010450:Endopeptidases; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
D020121:5' Untranslated Regions; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human