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Fig. 7 | Molecular Neurodegeneration

Fig. 7

From: Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

Fig. 7

SorCS2 signaling in neuronal networks relevant for AD. SorCS2 is found in neural soma, dendrites and axons. Box A) SorCS2 exists in three isoforms that have different signaling profiles. SorCS2 is initially produced as a proform, which can be cleaved by Furin from its propeptide, giving rise to a single-chain receptor. The single-chain can be further cleaved within the leucine-rich domain, producing a two-chain isoform. Box B) SorCS2 expression changes upon external stimuli, which affects synaptic plasticity. Box C) SorCS2 interactions with neurotrophins. 1. SorCS2 single-chain binds p75NTR and Trio, which mediates Rac1 and Fascin signaling. Fascin activation leads to F-actin filaments assembly and growth cone outgrowth. 2. ProBDNF or proNGF binding to SorCS2 leads to dissociation of Trio causing Rac1 signaling inactivation, actin filaments disassembly and retraction, and grow cone collapse, which is important for synaptic pruning and neuronal wirening. 3. Propeptide of BDNF-WT binding to SorCS2 does not affect the growth cone outgrowth. 4. Propeptide of BDNF with Val66Met mutation exhibits high binding affinity to SorCS2, subsequently dissociating Trio, and inhibiting Rac1 signaling. This pathway promotes elimination of spines and loss of synaptic adaptability. 5. SorCS2 two-chain binds p75NTR, which mediates proBDNF-dependent apoptosis. Box D) SorCS2 controls synaptic plasticity. Upon proBDNF release (1a.), SorCS2 mediates synaptic weakening (4a.) via its interaction with proBDNF and p75NTR (2a.), which induces long-term potentiation (LTD; 3a.). SorCS2 and the BDNF receptor TrkB are located outside of the postsynaptic density (PSD). Upon BDNF release (1b.), SorCS2 and TrkB relocate to the synapse (2b.) where they interact. TrkB binds BDNF, and undergoes phosphorylation and activation (3b.), subsequently inducing LTP (4b.) and synaptic strengthening (5b.). Box E) SorCS2 interacts with synaptic receptors GluN2A/2B, EAAT3, and TrkB at PSD of glutamergic neurons, and regulates their anterograde and retrograde trafficking. Impairments in these processes lead to increased cellular stress and neurodegeneration

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