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Büll, Dominik (2010): Die Repression der Translation der anti-amyloidogenen Sekretase ADAM10 durch die 5’-untranslatierte Region. Dissertation, LMU München: Faculty of Medicine
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Abstract

Proteolytic processing of the amyloid precursor protein (APP) by α-secretase prevents the formation of the amyloid β-peptide (Aβ), which is the main constituent of amyloid plaques in brains of Alzheimer's disease (AD) patients. In AD α-Secretase activity is decreased, and overexpression of the α-secretase ADAM10 (a disintegrin and metalloprotease 10) in an AD animal model prevents amyloid pathology. ADAM10 features a 444-nucleotide-long, very GC-rich 5′-untranslated region (5′UTR) with two upstream open reading frames. Because similar properties of 5′UTRs are found in transcripts of many genes, which are regulated by translational control mechanisms, we asked whether ADAM10 expression is translationally controlled by its 5′UTR. Here we demonstrate that the 5′UTR of ADAM10 represses the rate of ADAM10 translation. In the absence of the 5′UTR, we observed a significant increase of ADAM10 protein levels in HEK293 cells, whereas mRNA levels were unchanged. Moreover, the 5′UTR of ADAM10 inhibits translation of a luciferase reporter in an in vitro-transcription/-translation assay. Successive deletion of the first half of the ADAM10 5′UTR revealed a striking increase in ADAM10 protein expression in HEK293 cells, suggesting that this part of the 5′UTR contains inhibitory elements for translation. In contrast, the deletion of the 3'-part of the 5'UTR led to significantly reduced protein levels. Thus, we provide evidence that the 5′UTR of ADAM10 may have an important role for post-transcriptional regulation of ADAM10 expression. Therefore these findings might be of significant importance for future research in Alzheimer's disease and the development of novel therapeutic strategies of this devastating disorder.