Translational regulation of BACE-1 expression in neuronal and non-neuronal cells

Davide De Pietri Tonelli, Marija Mihailovich, Alessandra Di Cesare, Franca Codazzi, Fabio Grohovaz, Daniele Zacchetti

Research output: Contribution to journalArticle

Abstract

As the main beta-secretase of the central nervous syste, BACE-1 is a key protein in the pathogenesis of Alzheimer's disease. Excessive expression of the protein might cause an overproduction of the neurotoxic beta-amyloid peptide. Therefore, a tight regulation of BACE-1 expression is expected in vivo. In addition to a possible transcriptional control, the BACE-1 transcript leader contains features that might constitute mechanisms of translational regulation of protein expression. Moreover, recent work has revealed an increase of BACE-1 protein and beta-secretase activity in some Alzheimer's disease patients, although a corresponding increase of transcript has not been reported. Here we show that BACE-1 translation could be modulated at multiple stages. The presence of several upstream ATGs strongly reduces the translation of the main open reading frame. This inhibition could be overcome with conditions that favour skipping of upstream ATGs. We also report an alternative splicing of the BACE-1 transcript leader that reduces the number of upstream ATGs. Finally, we shoyv that translation driven by the BACE-1 transcript leader is increased in activated astrocytes independently of the splicing event, indicating yet another mechanism of translational control. Our findings might explain why increases in BACE-1 protein activity are reported in the brain of Alzheimer's disease patient even in the absence of changes in transcript levels.

Original languageEnglish
Pages (from-to)1808-1817
Number of pages10
JournalNucleic Acids Research
Volume32
Issue number5
DOIs
Publication statusPublished - 2004

ASJC Scopus subject areas

  • Genetics

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