Retromer Binds the FANSHY Sorting Motif in SorLA to Regulate Amyloid Precursor Protein Sorting and Processing

Overview

Journal J Neurosci

Specialty Neurology

Date 2012 Jan 27

PMID 22279231

Citations 150

Authors

Anja W Fjorback

Matthew Seaman

Camilla Gustafsen

Arnela Mehmedbasic

Suzanne Gokool

Chengbiao Wu

Daniel Militz

Vanessa Schmidt

Peder Madsen

Jens R Nyengaard

Thomas E Willnow

Erik Ilso Christensen

William B Mobley

Anders Nykjaer

Olav M Andersen

Affiliations

Soon will be listed here.

Abstract

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.

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