title: The Golgi-Localized γ-Ear-Containing ARF-Binding (GGA) Proteins Alter Amyloid-β Precursor Protein (APP) Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1).
abstract: Proteolytic processing of amyloid-β precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) is the initial step in the production of amyloid beta (Aβ), which accumulates in senile plaques in Alzheimer's disease (AD). Essential for this cleavage is the transport and sorting of both proteins through endosomal/Golgi compartments. Golgi-localized γ-ear-containing ARF-binding (GGA) proteins have striking cargo-sorting functions in these pathways. Recently, GGA1 and GGA3 were shown to interact with BACE1, to be expressed in neurons, and to be decreased in AD brain, whereas little is known about GGA2. Since GGA1 impacts Aβ generation by confining APP to the Golgi and perinuclear compartments, we tested whether all GGAs modulate BACE1 and APP transport and processing. We observed decreased levels of secreted APP alpha (sAPPα), sAPPβ, and Aβ upon GGA overexpression, which could be reverted by knockdown. GGA-BACE1 co-immunoprecipitation was impaired upon GGA-GAE but not VHS domain deletion. Autoinhibition of the GGA1-VHS domain was irrelevant for BACE1 interaction. Our data suggest that all three GGAs affect APP processing via the GGA-GAE domain.
authors.affiliation: Institute of Neurology, Ulm University, Helmholtzstraße 8/1, 89081 Ulm, Germany.
authors.forename: Bjoern
authors.initials: B
authors.lastname: von Einem
authors.affiliation: Institute of Neurology, Ulm University, Helmholtzstraße 8/1, 89081 Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Wahler
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schips
authors.affiliation: Massachusetts General Hospital Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Alberto
authors.initials: A
authors.lastname: Serrano-Pozo
authors.affiliation: Institute of Anatomy and Cell Biology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Proepper
authors.affiliation: Institute of Anatomy and Cell Biology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: Core Facility Laser Microscopy, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Rueck
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.affiliation: Massachusetts General Hospital Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Institute of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.affiliation: Laboratory for Neuropathology-Institute of Pathology, Ulm University, Helmholtzstraße 8/1, 89081, Ulm, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.affiliation: Institute of Neurology, Ulm University, Helmholtzstraße 8/1, 89081 Ulm, Germany.
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D005810:Multigene Family; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D017384:Sequence Deletion
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human