Sorting Out the Role of the Sortilin-Related Receptor 1 in Alzheimer's Disease

Abstract

Sortilin-related receptor 1 (SORL1) encodes a large, multi-domain containing, membrane-bound receptor involved in endosomal sorting of proteins between the trans-Golgi network, endosomes and the plasma membrane. It is genetically associated with Alzheimer's disease (AD), the most common form of dementia. SORL1 is a unique gene in AD, as it appears to show strong associations with the common, late-onset, sporadic form of AD and the rare, early-onset familial form of AD. Here, we review the genetics of SORL1 in AD and discuss potential roles it could play in AD pathogenesis.

Keywords: Alzheimer’s disease; amyloid; amyloid-beta protein precursor; endocytosis; endosomes; protein transport.

Fig.1

SORL1 encodes a multi-domain containing protein and its transcripts are subject to alternative splicing. (A) depicts gene models for alternative SORL1 splice products from the ENSEMBL database (ENSG00000137642) and published literature. Exons are numbered and color-coded to indicate which protein domains they encode. Protein-coding domains are as given for the human SORL1 protein (Uniprot ID: Q92673) with SMART database annotations. VPS10, vacuolar protein sorting 10; LDLR, low density lipoprotein receptor; EGF, epidermal growth factor. (B) depicts a schematic of the full length SORL1 protein consisting of a pro-peptide sequence, a VPS10 domain, five LDLR class B repeats, an EGF-like domain, eleven LDLR class A repeats, six fibronectin-type (FN) repeats, a transmembrane domain (TMD) and a cytosolic intracellular domain (ICD) containing recognition motifs for cytosolic adaptors. Binding sites of amyloid-β protein precursor (AβPP), amyloid-β (Aβ), sorting nexin 27 (SNX27), Golgi-localizing, γ-adaptin ear homology domain ARF-interaction (GGA), clathrin adaptor protein 1/2 (AP1/2), and phosphofurin acidic cluster sorting protein 1 (PACS1) and the nuclear localization signal (NLS) are indicated.

Fig.2

SORL1 trafficking pathways. Nascent SORL1 peptides are generated in the endoplasmic reticulum (ER) and follow the constituent secretory pathway to the trans-Golgi network (TGN) where the pro-peptide is removed by furin-mediated cleavage. This allows the receptor to move to the plasma membrane where it can follow a signaling pathway (left) or a trafficking pathway (right). In the signaling pathway, SORL1 is cleaved by tumor necrosis factor-A converting enzyme (TACE) and then by γ-secretase, releasing luminal fragments of SORL1 and a cytosolic SORL1 intracellular domain (SORL1-ICD). SORL1-ICD can move to the nucleus (N) and regulate transcription of as yet unknown genes. In the trafficking pathway, SORL1 can be internalized via clathrin-mediated endocytosis utilizing the chaperone clathrin adaptor protein 2 (AP2). Internalized SORL1 receptors then shuttle between the TGN and the endosomes, guided by cytosolic adaptor proteins such as adaptor protein 1 (AP1), phosphofurin acidic cluster sorting protein (PACS1), Golgi-localizing, γ-adaptin ear homology domain ARF-interaction (GGA) and the retromer complex.

Fig.3

EOfAD variants in SORL1. Figure 3 depicts a schematic of the SORL1 full length protein, indicating the sites for early-onset, familial Alzheimer’s disease (EOfAD) variants for which pedigrees have been published to date. Red arrows indicate variants published in [18] and blue arrows indicate variants published from [19]. VPS10, vacuolar protein sorting 10; LDLR, low density lipoprotein receptor; EGF, epidermal growth factor; FN, fibronectin-type; TMD, transmembrane domain; ICD, intracellular domain.

Fig.4

Proteolytic processing of AβPP. Membrane bound amyloid-β protein precursor (AβPP) can be subjected to non-amyloidogenic or amyloidogenic processing. In the non-amyloidogenic pathway, AβPP is first cleaved by α-secretase within the amyloid-β (Aβ) sequence, producing a soluble sAβPPα fragment and a membrane-bound C83 fragment. C83 can be processed further by the γ-secretase complex to give a p3 fragment and an AβPP intracellular domain (AICD). In the amyloidogenic pathway, AβPP can be cleaved by β-secretase, giving the C99 and sAβPPβ fragments. Then C99 is cleaved by γ-secretase to give Aβ peptides and an AICD. β-secretase and γ-secretase may function together as a supramolecular complex. Yellow depicts a lipid bi-layer and pink depicts a cytosolic region.

Fig.5

SORL1 dependent trafficking of AβPP. AβPP is translated at the endoplasmic reticulum (ER) and is processed in the Golgi for direction to the cell surface. Some AβPP is cleaved in the non-amyloidogenic pathway by α-secretase and some AβPP is internalized by clathrin-mediated endocytosis via the chaperone clathrin adaptor protein 2 (AP2). SORL1 is present in early endosomes and can guide AβPP throughout different pathways in the cell by interacting with different adaptor proteins. SORL1 and AβPP can move directly back to the plasma membrane (orange) mediated by sorting nexin 27 (SNX27). They can also move retrogradely to the trans-Golgi network (TGN) mediated by the retromer complex, clathrin adaptor protein 1 (AP1), and/or phosphofurin acidic cluster sorting protein (PACS1). They can also move anterogradely from the TGN to the early endosomes mediated by Golgi-localizing, γ-adaptin ear homology domain ARF-interaction (GGA) proteins. Without SORL1, AβPP can move to late endosomal compartments where some β- and γ-secretase activities are thought to be located and can be proteolytically cleaved to form Aβ. SORL1 can also bind newly-formed Aβ and direct it to the lysosome for degradation. SORL1, AβPP, β- and γ-secretases are also present in the mitochondrial associated membranes (MAMs) of the ER.