Expression of the β-secretase BACE1 is translationally suppressed
A9 - Haass & Schmid together with B12 - Lichtenthaler
The aspartyl protease BACE-1 has a pivotal role in the pathogenesis of AD as described above. Recently, it was shown that in AD patients, BACE-1 levels were elevated although mRNA levels were not changed compared with controls. In a collaborative effort of projects A9 (Haass & Schmid) and B12 (Lichtenthaler) it could be demonstrated that the 5‘-untranslated region (5‘UTR) of BACE1 controls the rate of BACE1 translation. In the presence of the 5‘UTR, a more than 90% reduction of BACE1 protein levels in cells, and a similar reduction of BACE1 activity in vitro could be observed. mRNA levels were not affected, demonstrating that the 5‘UTR repressed the translation but not the transcription of BACE1. The 3‘UTR did not affect BACE1 expression. An extensive mutagenesis analysis predicts that the GC-rich region of the 5‘UTR forms a constitutive translation barrier, which may prevent the ribosome from efficiently translating the BACE-1 mRNA. These data therefore demonstrate translational repression as a new mechanism controlling BACE-1 expression. These findings were published in EMBO Reports (Lammich et al., 2004) and provide the basis for a new aim in project A9.