| First Author | Burgert T | Year | 2013 |
| Journal | Mol Cell Biol | Volume | 33 |
| Issue | 21 | Pages | 4308-20 |
| PubMed ID | 24001769 | Mgi Jnum | J:205418 |
| Mgi Id | MGI:5544849 | Doi | 10.1128/MCB.00628-13 |
| Citation | Burgert T, et al. (2013) SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes. Mol Cell Biol 33(21):4308-20 |
| abstractText | Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into Abeta 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 Abeta. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms. |
