Helmholtz Gemeinschaft


Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain

[img] PDF (Original article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader

Item Type:Article
Title:Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain
Creators Name:Dumanis, S.B. and Burgert, T. and Caglayan, S. and Füchtbauer, A. and Füchtbauer, E.M. and Schmidt, V. and Willnow, T.E.
Abstract:SORLA is a neuronal sorting receptor implicated both in sporadic and familial forms of AD. SORLA reduces the amyloidogenic burden by two mechanisms, either by rerouting internalized APP molecules from endosomes to the trans-Golgi network (TGN) to prevent proteolytic processing or by directing newly produced Aβ to lysosomes for catabolism. Studies in cell lines suggested that the interaction of SORLA with cytosolic adaptors retromer and GGA is required for receptor sorting to and from the TGN. However, the relevance of anterograde or retrograde trafficking for SORLA activity in vivo remained largely unexplored. Here, we generated mouse models expressing SORLA variants lacking binding sites for GGA or retromer to query this concept in the brain. Disruption of retromer binding resulted in a retrograde-sorting defect with accumulation of SORLA in endosomes and depletion from the TGN, and in an overall enhanced APP processing. In contrast, disruption of the GGA interaction did not impact APP processing but caused increased brain Aβ levels, a mechanism attributed to a defect in anterograde lysosomal targeting of Aβ. Our findings substantiated the significance of adaptor-mediated sorting for SORLA activities in vivo, and they uncovered that anterograde and retrograde sorting paths may serve discrete receptor functions in amyloidogenic processes.
Keywords:Adaptors, APP Processing, Protein Transport, Retromer, SORLA, VPS10P Domain Receptors, Animals, Mice
Source:Journal of Neuroscience
Publisher:Society for Neuroscience
Page Range:12703-12713
Date:16 September 2015
Official Publication:https://doi.org/10.1523/JNEUROSCI.0427-15.2015
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library