Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing

被引：80
作者：
Dinamarca, Margarita C. [1 ]
Raveh, Adi [1 ]
Schneider, Andy [2 ]
Fritzius, Thorsten [1 ]
Frueh, Simon [1 ]
Rem, Pascal D. [1 ]
Stawarski, Michal [1 ]
Lalanne, Txomin [1 ]
Turecek, Rostislav [1 ,6 ]
Choo, Myeongjeong [1 ]
Besseyrias, Valerie [1 ]
Bildl, Wolfgang [2 ]
Bentrop, Detlef [2 ]
Staufenbiel, Matthias [3 ]
Gassmann, Martin [1 ]
Fakler, Bernd [2 ,4 ,5 ]
Schwenk, Jochen [2 ,4 ,5 ]
Bettler, Bernhard [1 ]
机构：
[1] Univ Basel, Inst Physiol, Dept Biomed, Klingelbergstr 50-70, CH-4056 Basel, Switzerland
[2] Univ Freiburg, Fac Med, Inst Physiol, Hermann Herder Str 7, D-79104 Freiburg, Germany
[3] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Cellular Neurol, Otfried Muller Str 27, D-72076 Tubingen, Germany
[4] Univ Freiburg, Signalling Res Ctr BIOSS, Schanzlestr 18, D-79104 Freiburg, Germany
[5] Univ Freiburg, Signalling Res Ctr CIBSS, Schanzlestr 18, D-79104 Freiburg, Germany
[6] ASCR, Inst Expt Med, Videnska 1083, Prague 14220 4, Czech Republic
来源：
NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期
基金：
瑞士国家科学基金会;
关键词：
PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; SUSHI DOMAINS; B RECEPTORS; IN-VIVO; TRANSPORT; RELEASE; PHOSPHORYLATION; IDENTIFICATION; ENDOCYTOSIS;
D O I：
10.1038/s41467-019-09164-3
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
GABA(B) 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 A beta, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to A beta formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases A beta formation.
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页数：17
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