Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow Print PDF (356K) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Right arrow Articles by De Pietri Tonelli, D.
Right arrow Articles by Zacchetti, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Pietri Tonelli, D.
Right arrow Articles by Zacchetti, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published online 19 March 2004

Nucleic Acids Research, 2004, Vol. 32, No. 5 1808-1817
Oxford University Press

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

Davide De Pietri Tonelli1, Marija Mihailovich1,2, Alessandra Di Cesare1,2, Franca Codazzi1, Fabio Grohovaz1,2 and Daniele Zacchetti*,1

1 Cellular Neurophysiology Unit, Department of Neuroscience, San Raffaele Scientific Institute and 2 Vita-Salute San Raffaele University, via Olgettina 58, I-20132 Milano, Italy

*To whom correspondence should be addressed. Tel: +39 02 2643 4817; Fax: +39 02 2643 4813; Email: zacchetti.daniele{at}hsr.it
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

Received September 25, 2003; Revised December 5, 2003; Accepted March 2, 2004

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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 DNA ResHome page
A. Wakamatsu, K. Kimura, J.-i. Yamamoto, T. Nishikawa, N. Nomura, S. Sugano, and T. Isogai
Identification and Functional Analyses of 11 769 Full-length Human cDNAs Focused on Alternative Splicing
DNA Res, December 1, 2009; 16(6): 371 - 383.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Watatani, K. Ichikawa, N. Nakanishi, M. Fujimoto, H. Takeda, N. Kimura, H. Hirose, S. Takahashi, and Y. Takahashi
Stress-induced Translation of ATF5 mRNA Is Regulated by the 5'-Untranslated Region
J. Biol. Chem., February 1, 2008; 283(5): 2543 - 2553.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. Mihailovich, R. Thermann, F. Grohovaz, M. W. Hentze, and D. Zacchetti
Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5' untranslated region
Nucleic Acids Res., May 14, 2007; 35(9): 2975 - 2985.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
X. Sun, Y. Tong, H. Qing, C.-H. Chen, and W. Song
Increased BACE1 maturation contributes to the pathogenesis of Alzheimer's disease in Down syndrome
FASEB J, July 1, 2006; 20(9): 1361 - 1368.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
W. Zhou and W. Song
Leaky Scanning and Reinitiation Regulate BACE1 Gene Expression.
Mol. Cell. Biol., May 1, 2006; 26(9): 3353 - 3364.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
V. Wiesenthal, A. Leutz, and C. F. Calkhoven
A translation control reporter system (TCRS) for the analysis of translationally controlled processes in the vertebrate cell
Nucleic Acids Res., February 10, 2006; 34(3): e23 - e23.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
R. A. Velliquette, T. O'Connor, and R. Vassar
Energy Inhibition Elevates {beta}-Secretase Levels and Activity and Is Potentially Amyloidogenic in APP Transgenic Mice: Possible Early Events in Alzheimer's Disease Pathogenesis
J. Neurosci., November 23, 2005; 25(47): 10874 - 10883.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.