A novel beta-site amyloid precursor protein cleaving enzyme (BACE) isoform regulated by nonsense-mediated mRNA decay and proteasome-dependent degradation

doi:10.1016/j.neulet.2007.09.033

Neuroscience Letters

Volume 428, Issues 2–3, 27 November 2007, Pages 103-108

https://doi.org/10.1016/j.neulet.2007.09.033 Get rights and content

Abstract

Proteolytic cleavage of amyloid beta-peptide (Aβ) from amyloid precursor protein (APP) is a key event in the pathogenesis of Alzheimer's disease. Beta-site amyloid precursor protein cleaving enzyme (BACE) cleaves the APP at the N-terminus of Aβ. We investigated whether particular stress conditions modify the expression and activity of BACE, and found that treatment of human neuroblastoma cells with protein synthesis inhibitors induced expression of a novel splice variant of BACE. This unusual transcript, I-127, is produced by usage of an internal splicing donor site in exon 3. The splicing event leads to a premature termination codon, as well as elimination of one of two conserved aspartic protease active sites, a transmembrane domain, and a C-terminal cytoplasmic tail from BACE. Low levels of this mRNA were found in the human brain. When expressed in cells, I-127 had no effect on Aβ secretion and was retained in the endoplasmic reticulum without propeptide removal. It was also unstable with a turnover t_1/2 of ∼2 h; normal BACE had a turnover t_1/2 of ∼8 h. Finally, I-127 was degraded in a proteasome-dependent manner. Thus, I-127 is regulated by both nonsense-mediated mRNA decay (NMD) and proteasome-dependent degradation.

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Acknowledgements

We thank Dr. N. Suzuki and A. Asami-Odaka (Takeda Pharmaceutical Co., Japan) for providing antibodies BAN-50, BA-27, and BC-05. This work was partly supported by grants to H.T. from the Japanese Ministry of Education, Culture, Science and Sports (17590242).

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A novel beta-site amyloid precursor protein cleaving enzyme (BACE) isoform regulated by nonsense-mediated mRNA decay and proteasome-dependent degradation

Abstract

Section snippets

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Lett.

Molecular analysis of the presenilin 1 (S182) gene in “Sporadic” cases of Alzheimer's disease: Identification and characterization of unusual splice variants

J. Neurochem.

Neuronal expression of GFAP in patients with Alzheimer pathology and identification of novel GFAP splice form

Mol. Psychiatry

Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease

J. Neurochem.