Sunday Driver Mediates Multi-Compartment Golgi Outposts Defects Induced by Amyloid Precursor Protein

Golgi defects including Golgi fragmentation are pathological features of Alzheimer’s disease (AD). As a pathogenic factor in AD, amyloid precursor protein (APP) induces Golgi fragmentation in the soma. However, how APP regulates Golgi outposts (GOs) in dendrites remains unclear. Given that APP resides in and affects the movements of GOs, and in particular, reverses the distribution of multi-compartment GOs (mcGOs), we investigated the regulatory mechanism of mcGO movements in the Drosophila larvae. Knockdown experiments showed that the bidirectional mcGO movements were cooperatively controlled by the dynein heavy chain (Dhc) and kinesin heavy chain subunits. Notably, only Dhc mediated APP’s regulation of mcGO movements. Furthermore, by loss-of-function screening, the adaptor protein Sunday driver (Syd) was identified to mediate the APP-induced alteration of the direction of mcGO movements and dendritic defects. Collectively, by elucidating a model of bidirectional mcGO movements, we revealed the mechanism by which APP regulates the direction of mcGO movements. Our study therefore provides new insights into AD pathogenesis.

Download Full-text

Faculty Opinions recommendation of β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717967660.793466211 ◽

2012 ◽

Author(s):

Robert Petersen

Keyword(s):

Amyloid Precursor Protein ◽

Axon Guidance ◽

Precursor Protein ◽

Loss Of Function ◽

Deficient Mice ◽

Close Homolog

Download Full-text

Amyloid-β Peptide Exacerbates the Memory Deficit Caused by Amyloid Precursor Protein Loss-of-Function in Drosophila

PLoS ONE ◽

10.1371/journal.pone.0135741 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0135741 ◽

Cited By ~ 6

Author(s):

Isabelle Bourdet ◽

Aurélie Lampin-Saint-Amaux ◽

Thomas Preat ◽

Valérie Goguel

Keyword(s):

Amyloid Precursor Protein ◽

Amyloid Β ◽

Memory Deficit ◽

Precursor Protein ◽

Amyloid Β Peptide ◽

Loss Of Function ◽

Protein Loss

Download Full-text

Adaptor protein 2–mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing

Molecular Biology of the Cell ◽

10.1091/mbc.e11-11-0944 ◽

2012 ◽

Vol 23 (12) ◽

pp. 2339-2351 ◽

Cited By ~ 46

Author(s):

Yogikala Prabhu ◽

Patricia V. Burgos ◽

Christina Schindler ◽

Ginny G. Farías ◽

Javier G. Magadán ◽

...

Keyword(s):

Plasma Membrane ◽

Amyloid Precursor Protein ◽

Secretory Pathway ◽

Brefeldin A ◽

Adaptor Protein ◽

Proteolytic Processing ◽

Precursor Protein ◽

Amyloid Precursor Protein Processing ◽

Intermediate Compartment ◽

Golgi Network

The β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.

Download Full-text