Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing
| Autor: | Dinamarca, Margarita C., Raveh, Adi, Schneider, Andy, Fritzius, Thorsten, Früh, Simon, Rem, Pascal D., Stawarski, Michal, Lalanne, Txomin, Turecek, Rostislav, Choo, Myeongjeong, Besseyrias, Valérie, Bildl, Wolfgang, Bentrop, Detlef, Staufenbiel, Matthias, Gassmann, Martin, Fakler, Bernd, Schwenk, Jochen, Bettler, Bernhard |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Proteomics
Amyloid Science Kinesins Nerve Tissue Proteins Axonal Transport Article Epitopes GTP-Binding Proteins mental disorders Animals Humans Amino Acid Sequence lcsh:Science Amyloid beta-Peptides Protein Stability Cell Membrane Dendrites Axons Mice Inbred C57BL HEK293 Cells nervous system Receptors GABA-B Synapses lcsh:Q Cell Adhesion Molecules Protein Binding Signal Transduction |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019) |
| ISSN: | 2041-1723 |
| Popis: | GABAB receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aβ, a component of senile plaques in Alzheimer’s disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer’s disease increases Aβ formation. The mechanisms that control the presynaptic abundance of GABAB receptors (GBRs) remains unclear. This study shows that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs, and that selective loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression |
| Databáze: | OpenAIRE |
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