SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes
| Autor: | Anne-Sophie Carlo, Tilman Burgert, Thomas E. Willnow, Anders Nykjaer, Annette Füchtbauer, Safak Caglayan, Ernst-Martin Füchtbauer, Vanessa Schmidt, Fuyu Lin |
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| Rok vydání: | 2013 |
| Předmět: |
Endosome
Molecular Sequence Data Vesicular Transport Proteins Mice Transgenic Plasma protein binding medicine.disease_cause Receptor IGF Type 2 Cathepsin B Amyloid beta-Protein Precursor Mice Cell Line Tumor Protein targeting Amyloid precursor protein medicine Animals Humans Protein Interaction Domains and Motifs Amino Acid Sequence education Molecular Biology LDL-Receptor Related Proteins Neurons education.field_of_study biology Brain Membrane Transport Proteins Articles Cell Biology Transport protein Cell biology Protein Transport Biochemistry Gene Knockdown Techniques Phosphofurin acidic cluster sorting protein 1 biology.protein Intracellular Protein Binding |
| Zdroj: | Burgert, T, Schmidt, V, Caglayan, S, Lin, F, Füchtbauer, A, Füchtbauer, E-M, Nykjaer, A, Carlo, A-S & Willnow, T E 2013, ' SORLA-Dependent and-Independent Functions for PACS1 in Control of Amyloidogenic Processes ', Molecular and Cellular Biology, vol. 33, no. 21, pp. 4308-4320 . https://doi.org/10.1128/MCB.00628-13 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00628-13 |
| Popis: | Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into Aβ peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons and in increased APP processing in the brain. Loss of PACS1 also impairs the proper expression of the cation-independent mannose 6-phosphate receptor and its target cathepsin B, a protease that breaks down Aβ. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms. |
| Databáze: | OpenAIRE |
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