SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Abstract

c Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into A␤ 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 A␤. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.

SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity

“…SORLA is a sorting receptor that shuttles between endosomes and the TGN to sort target proteins between endocytic and secretory compartments of the cell. Shuttling of SORLA is guided by the adaptors GGA, PACS1, and retromer, which bind to the cytoplasmic tail of the receptor and direct its movement from endosomes to the TGN and back (24,25). The relevance of SORLA-mediated protein sorting has best been elucidated for APP in AD.…”

Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation

“…PACS1 and the retromer complex that sort cargo between Golgi and late endosomes/lysosomes (27,28,35,36). Also, SORLA has been shown to bind to the lipolytic enzyme lipoprotein lipase in the biosynthetic pathway of neurons and to direct it for lysosomal degradation (24).…”

Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability

“…Since the retrieval mechanism of the IGF-II receptor from endosomes to TGN overlaps with that of APP and BACE1, it is plausible that changes introduced by overexpression of the IGF-II receptor, such as an increase of APP in lipid rafts, facilitates the processing of APP within endosomal compartments, leading to the increased production of A␤ peptides. Apart from regulating APP processing, IGF-II receptor overexpression decreased the levels of the A␤ degrading enzyme IDE but not those of neprilysin, which also may contribute to an increase in A␤ levels in the conditioned media by prolonging its half-life (71,73). Although the significance of continued IGF-II receptor overexpression on APP and BACE1 levels as well as APP processing have been validated by receptor siRNA treatment of MS9II cells in the present study, the functional implications of normal levels of the IGF-II receptor on A␤ metabolism remains to be evaluated in future experiments.…”

“…APP can be retrieved from endosomes back to TGN by binding to a sorting-related receptor with A-type repeats (SORLA) via PACS1, thereby preventing its processing into A␤ peptides (6,68). The loss of PACS1 expression or deletion of the PACS1 binding site in SORLA results in increased accumulation and processing of APP in the endosomal compartments (70,71). Like APP, retrograde transport of BACE1 from endosomes to TGN, as observed for the IGF-II receptor, is mediated by binding to GGA proteins and the retromer complex.…”