VPS10P Domain Receptors: Sorting Out Brain Health and Disease

Malik, Anna R.; Willnow, Thomas E.

doi:10.1016/j.tins.2020.08.003

Cited by 42 publications

(72 citation statements)

References 108 publications

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“…Strikingly, the interaction between SorCS2 and GluN2B is dynamic in MSNs as BDNF disrupted the complexes. SorCS2 is engaged in several aspects of protein sorting directing its cargo between Golgi, cell surface and endosomes (36). Notably, we found that SorCS2 facilitates the synaptic translocation of TrkB to postsynaptic densities in hippocampal neurons (33).…”

Section: Discussionmentioning

confidence: 76%

SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington’s disease progression

Salašová

Degn

Paveliev

et al. 2021

Preprint

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BackgroundHuntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Mutations in BDNF receptor SorCS2 were recently identified in HD patients. Our study investigates the role of SorCS2 in MSNs biology and in HD progression.MethodsWe derived a double transgenic line by crossbreeding SorCS2 deficient (KO) mice with the HD mouse model R6/1. Subsequently, we characterized the SorCS2 KO; R6/1 line by a set of behavioral and biochemical studies to evaluate phenotypes related to HD. Moreover, in combination with electrophysiology and super resolution microscopy techniques, we addressed the molecular mechanism by which SorCS2 controls synaptic activity in MSNs neurons.ResultsWe show that SorCS2 is expressed in MSNs with reduced levels in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. However, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice.ConclusionsWe formulate a novel molecular mechanism by which SorCS2 acts as a molecular switch. SorCS2 targets TrkB and GluN2B into postsynaptic densities to enable BDNF signaling and NMDAR dependent neurotransmission in the dorsal striatum. Remarkably, the binding between SorCS2 and TrkB or GluN2B, respectively, is mutually exclusive and controlled by BDNF. This mechanism provides an explanation why deficient SorCS2 signaling severely aggravates HD progression in mice. Moreover, we provide evidence that this finding might represent a general mechanism of SorCS2 signaling found in other brain areas, thus increasing its relevance for other neurological and psychiatric impairments.

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Section: Discussionmentioning

confidence: 76%

SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington’s disease progression

Salašová

Degn

Paveliev

et al. 2021

Preprint

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“…Cargo receptors play a role at multiple sites in the secretory pathway (Fig. 7) [28,[154][155][156][157].…”

Section: Accepted Articlementioning

confidence: 99%

“…These same factors are likely to control the ability of PAM to interact with proANP. Sortilin-family members, which include at least one luminal vacuolar protein sorting 10 protein (VPS10P) domain, function as cargo transporters at multiple steps within the biosynthetic and endocytic pathways [156,157] (Fig. 7).…”

Section: Accepted Articlementioning

confidence: 99%

“…The short, unstructured cytoplasmic domains of PAM and Sortilin include acidic clusters and binding sites for AP1, AP2 [36,157] and other cytoplasmic trafficking components. Sortilin, like PAM, is targeted to MVBs and released in exosomes [137,138,157]. Its VPS10P domain forms a ten-bladed propeller, with multiple binding sites located within its funnel-like structure [158].…”

Section: Accepted Articlementioning

confidence: 99%

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PAM: diverse roles in neuroendocrine cells, cardiomyocytes, and green algae

2021

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Our understanding of the ways in which peptides are used for communication in the nervous and endocrine systems began with the identification of oxytocin, vasopressin and insulin, each of which is stored in electron dense granules, ready for release in response to an appropriate stimulus. For each of these peptides, entry of its newly synthesized precursor into the endoplasmic reticulum lumen is followed by transport through the secretory pathway, exposing the precursor to a sequence of environments and enzymes that produce the bioactive products stored in mature granules. A final step in the biosynthesis of many peptides is C-terminal amidation by Peptidylglycine -Amidating Monooxygenase (PAM), an ascorbate-and copper-dependent membrane enzyme that enters secretory granules along with its soluble substrates. Biochemical and cell biological studies elucidated the highly conserved mechanism for amidated peptide production and raised many questions about PAM trafficking and the effects of PAM on cytoskeletal organization and gene expression. Phylogenetic studies and the discovery of active PAM in the ciliary membranes of Chlamydomonas reinhardtii, a green alga lacking secretory granules, suggested that a PAM-like enzyme was present in the last eukaryotic common ancestor. While the catalytic features of human and C. reinhardtii PAM are strikingly similar, the trafficking of PAM in C. reinhardtii and neuroendocrine cells and secretion of its amidated products differ. A comparison of PAM function in neuroendocrine cells, atrial myocytes and C. reinhardtii reveals multiple ways in which altered trafficking allows PAM to accomplish different tasks in different species and cell-types.This article is protected by copyright. All rights reserved encoding their precursors revealed the importance of post-translational processing in the production of bioactive peptides [5,6]. With the identification of COOH-terminal amidation as a critical step in the synthesis of peptides like vasopressin, oxytocin, neuropeptide Y, cholecystokinin and -melanocyte stimulating hormone, searches for an amidating enzyme began [7][8][9]. The sequencing of cDNAs encoding the prepropeptides for amidated peptides indicated that each amidated peptide was produced from a precursor with a COOH-terminal glycine.Using bovine and rodent pituitaries, a soluble monooxygenase that converted peptidylglycine substrates into amidated products, peptidylglycine -hydroxylating monooxygenase (PHM; E.C. 1.14.17.3), was identified and shown to require copper and ascorbic acid (Fig. 1A) [9]. The purification of soluble, ~40 kDa PHM led to the expression cloning of a cDNA that encoded a 110 kDa Type I integral membrane protein that included an NH 2terminal signal sequence followed by PHM (Fig. 1A) [10]. With a cDNA in hand, it quickly became apparent that the luminal region of this membrane protein included two catalytic activities, PHM and peptidyl-hydroxyglycine -amidating lyase (PAL; E.C. 4.3.2.5) (Fig. 1A) [7,11]. Under the slightly acidic conditions encountere...

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“…Sortilin-related receptor (SorLA) is an intracellular sorting protein and a member of the family of vacuolar protein sorting 10 protein (VPS10P)-domain receptors (12). The Nterminal SorLA extracellular/luminal part contains multiple subdomains shown to mediate ligand binding/discharge, while the short C-terminal tail, containing trafficking signals, binds to cytosolic adaptor proteins to assemble protein complexes orchestrating SorLA traffic (13)(14)(15). The mature SorLA protein resides mainly in the trans-Golgi network and undergoes constitutive antero-and retrograde trafficking to the plasma membrane through endosomes.…”

Section: Introductionmentioning

confidence: 99%

Sortilin-related receptor is a druggable therapeutic target in breast cancer

Al‐Akhrass

Pietilä

Lilja

et al. 2021

Preprint

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In breast cancer, the currently approved anti-receptor tyrosine-protein kinase erbB-2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2-related therapeutic targets could offer means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin-related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2-targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti-SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cellularity in a mouse xenograft model of HER2-positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient-derived explant three-dimensional cultures. These results provide for the first time proof-of-principle that SorLA is a druggable target in breast cancer.

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VPS10P Domain Receptors: Sorting Out Brain Health and Disease

Cited by 42 publications

References 108 publications

SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington’s disease progression

SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington’s disease progression

PAM: diverse roles in neuroendocrine cells, cardiomyocytes, and green algae

Sortilin-related receptor is a druggable therapeutic target in breast cancer

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