SorLA/LR11 Regulates Processing of Amyloid Precursor Protein via Interaction with Adaptors GGA and PACS-1

Abstract

SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/ trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid ␤-peptide formation.

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

“…The physiological function of these interactions is not fully understood, but the current model suggests that these receptors bind APP at the cell surface and release APP in the endosome to regulate its internalization (57)(58)(59)(60)(61). Based on our previous work, we have proposed a model in which SorLA does not contribute to APP endocytosis but instead associates with APP in intracellular vesicles (10,22,23). This suggestion raised the interesting question of how SorLA remains associated with APP in a more acidic environment, whereas APP dissociates from other CRdomains (e.g.…”

“…SorLA binds directly to APP and slows down its cellular transport out of the Golgi; thus, less of the precursor protein enters secretase-containing compartments, decreasing the processing of APP to both nonamyloidogenic (sAPP␣) and amyloidogenic (A␤) products (10,11,(21)(22)(23). This function is dependent on receptor localization to the Golgi, establishing a direct link to the trafficking pathway from endosomes to the trans-Golgi network/Golgi, a pathway suspected to be altered in sporadic AD (2,24,25).…”

“…Although SorLA plays a direct role as a Golgi-localized retention factor that influences the amount of APP processed in sub- JOURNAL OF BIOLOGICAL CHEMISTRY 3363 sequent cellular compartments (22), it remains unknown whether SorLA overexpression per se affects the processing machinery, i.e. whether SorLA also works as a competitive substrate of the secretases that cleave APP, thereby diminishing A␤ production.…”

BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin

“…SorLA has been found to interact directly with APP and co-localize primarily in the Golgi (36,37). The effect of SorLA on APP appears to be the sequestration of APP to the TGN, inhibiting APP exit to the cell surface, as mediated by the SorLA cytoplasmic domain (36,57). Whereas SorLA appears to regulate APP distribution and processing through its interaction with APP, sortilin appears to regulate APP processing by its interaction with BACE1 and modulation of BACE1 trafficking.…”

Trafficking and Proteolytic Processing of APP

“…In addition, Ran-binding protein 9 promotes APP interaction with APP and facilitates APP internalization in a Fe65-independent manner (Lakshmana et al 2009). Finally, the type I transmembrane protein sorLA/LR11 (a member of the VPS10p-domain receptor family), which functionally interacts with cytosolic adaptors GGA and PACS-1, regulates Ab production by acting as a Golgi/TGN retention factor for APP (Andersen et al 2005;Offe et al 2006;Schmidt et al 2007). Ab levels are reduced on overexpression of sorLA/LR11 in cultured cells and increased in the brains of sorLA/ LR11 knockout mice (Andersen et al 2005;Offe et al 2006).…”