GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing.
The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.
von Arnim
Christine A F
CA
Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Spoelgen
Robert
R
Peltan
Ithan D
ID
Deng
Meihua
M
Courchesne
Stephanie
S
Koker
Mirjam
M
Matsui
Toshifumi
T
Kowa
Hisatomo
H
Lichtenthaler
Stefan F
SF
Irizarry
Michael C
MC
Hyman
Bradley T
BT
D020727:ADP-Ribosylation Factors / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001923:Brain Chemistry; D002460:Cell Line; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014162:Transfection
D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D020727:ADP-Ribosylation Factors