SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1.
SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid beta-peptide formation.
Schmidt
Vanessa
V
Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, Berlin, Germany.
Sporbert
Anje
A
Rohe
Michael
M
Reimer
Tatjana
T
Rehm
Armin
A
Andersen
Olav M
OM
Willnow
Thomas E
TE
D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C491914:PACS1 protein, human; C102582:SORL1 protein, human; D033921:Vesicular Transport Proteins; D020727:ADP-Ribosylation Factors