Complex formation of APP with GABA(B) receptors links axonal trafficking to amyloidogenic processing

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F19%3A00508267" target="_blank" >RIV/68378041:_____/19:00508267 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.nature.com/articles/s41467-019-09164-3" target="_blank" >https://www.nature.com/articles/s41467-019-09164-3</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-019-09164-3" target="_blank" >10.1038/s41467-019-09164-3</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Complex formation of APP with GABA(B) receptors links axonal trafficking to amyloidogenic processing

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Complex formation of APP with GABA(B) receptors links axonal trafficking to amyloidogenic processing

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/GA16-17823S" target="_blank" >GA16-17823S: Úloha GABAB receptorů ve zvířecích modelech tinitu</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

—

Svazek periodika

10

Číslo periodika v rámci svazku

mar

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

17

Strana od-do

1331

Kód UT WoS článku

000461995800002

EID výsledku v databázi Scopus

2-s2.0-85063319718