Translational regulation of BACE-1 expression in neuronal and non-neuronal cells.
As the main beta-secretase of the central nervous system, 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 show 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 or activity are reported in the brain of Alzheimer's disease patients even in the absence of changes in transcript levels.
De Pietri Tonelli
Davide
D
Cellular Neurophysiology Unit, Department of Neuroscience, San Raffaele Scientific InstituteMilano, Italy.
Mihailovich
Marija
M
Di Cesare
Alessandra
A
Codazzi
Franca
F
Grohovaz
Fabio
F
Zacchetti
Daniele
D
D020121:5' Untranslated Regions / Q000737:chemistry / Q000378:metabolism; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D001253:Astrocytes / Q000201:enzymology*; D002460:Cell Line; D010450:Endopeptidases; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis
D020121:5' Untranslated Regions; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human