SorLA/LR11 Regulates Processing of Amyloid Precursor Protein via Interaction with Adaptors GGA and PACS-1

Vanessa Schmidt,Anje Sporbert,Michael Rohe,Tatjana Reimer,Armin Rehm,Olav M Andersen,Thomas E Willnow

doi:10.1074/jbc.m705073200

Vanessa Schmidt, Anje Sporbert + Show 5 more

Open Access

https://doi.org/10.1074/jbc.m705073200

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Abstract

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.

Highlights

Golgi network (TGN) and early endosomes (4)
The significance of sorLA as negative regulator of amyloid precursor protein (APP) processing in vivo is supported by studies in sorLA-deficient mice that exhibit significantly higher levels of A␤ in the brain compared with control animals (6), similar to the situation seen in patients with sporadic Alzheimer disease (AD) that lack receptor expression (13, 14)
To dissect which step in the intracellular transport route of APP may be influenced by sorLA, we studied its trafficking through the secretory and endocytic compartments in Chinese hamster ovary (CHO) and in human neuronal SH-SY5Y cells in the presence or absence of sorLA

Summary

Introduction

Golgi network (TGN) and early endosomes (4). the exact trafficking route of sorLA has not been established yet, related members of the gene family were shown to move to the cell surface, internalize once, and thereafter shuttle between TGN and endosomal compartments (5). As well as regulating export of APP from the trans-Golgi/ TGN, sorLA may affect retrograde trafficking of precursor molecules internalized from the cell surface to this compartment.

Results

Conclusion