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Cysteine 27 variant of the delta-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons50098

Bertram,  L.
Neuropsychiatric Genetics (Lars Bertram), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Sarajarvi, T., Tuusa, J. T., Haapasalo, A., Lackman, J. J., Sormunen, R., Helisalmi, S., et al. (2011). Cysteine 27 variant of the delta-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking. Molecular and Cellular Biology, 31(11), 2326-40. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21464208 http://mcb.asm.org/content/31/11/2326.full.pdf.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-7892-8
Abstract
Agonist-induced activation of the delta-opioid receptor (deltaOR) was recently shown to augment beta- and gamma-secretase activities, which increased the production of beta-amyloid peptide (Abeta), known to accumulate in the brain tissues of Alzheimer's disease (AD) patients. Previously, the deltaOR variant with a phenylalanine at position 27 (deltaOR-Phe27) exhibited more efficient receptor maturation and higher stability at the cell surface than did the less common cysteine (deltaOR-Cys27) variant. For this study, we expressed these variants in human SH-SY5Y and HEK293 cells expressing exogenous or endogenous amyloid precursor protein (APP) and assessed the effects on APP processing. Expression of deltaOR-Cys27, but not deltaOR-Phe27, resulted in a robust accumulation of the APP C83 C-terminal fragment and the APP intracellular domain, while the total soluble APP and, particularly, the beta-amyloid 40 levels were decreased. These changes upon deltaOR-Cys27 expression coincided with decreased localization of APP C-terminal fragments in late endosomes and lysosomes. Importantly, a long-term treatment with a subset of deltaOR-specific ligands or a c-Src tyrosine kinase inhibitor suppressed the deltaOR-Cys27-induced APP phenotype. These data suggest that an increased constitutive internalization and/or concurrent signaling of the deltaOR-Cys27 variant affects APP processing through altered endocytic trafficking of APP.