In Alzheimer's disease, the formation of the amyloid � (A�) hallmark depends on the rate-limiting cleavage of amyloid precursor protein (APP) by beta-site APP-cleaving enzyme 1 (BACE1).  The 5' untranslated region (5'UTR) of BACE1 messenger RNA (mRNA) is known to be GC-rich and to contain four upstream translation initiation codons (uAUGs), which play important inhibitory roles in BACE1 translation.  In this study, we investigated the base composition and sequence of the BACE1 5'UTR in several species of mammals.  Three major characteristics have been discovered.  First, the BACE1 5'UTR contains more cytosine than guanine.  Next, the second upstream open reading frame (uORF) is extremely GC-rich.  Finally, the second uAUG is immediately followed by a C-rich motif that may adopt a complex secondary structure under acidic pathological conditions, and thus block/reduce the accessibility of the adjacent AUG to scanning ribosomes.  Other C-rich stretches present in the BACE1 5'UTR, such as the one near the 5'end, may contribute to the complete/partial bypass of the 5'UTR by scanning ribosomes and the significant increase in BACE1 protein expression in brains of patients with Alzheimer's disease.

Base composition and sequence characteristics of the 5'UTR of BACE1 mRNA

247th National Meeting (2014)

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