Fig. 6

SorCS1 localization and signaling relevant to AD. SorCS1 localization is restricted to cell soma and dendrites. Box A) SorCS1 forms homodimers, but also heterodimers with Sortilin via SorCS1 prodomain, and with SorCS2/3. Box B) SorCS1 binds APP in vesicular compartments; however, SorCS1 variants control APP sorting in different manner. While SorCS1b mediates APP trafficking towards PM, SorCS1c blocks it. Box C) SorCS1 binds TrkB, which inhibits TrkB activation by BDNF stimulation. SorCS1 might be responsible (marked “?”) for TrkB sorting between TGN, PM and recycling pathway. Box D) This figure schematizes the possible consequences of SorCS1 loss and gain of function. In homeostatic state (middle panel), SorCS1 binds APP and the retromer complex via its VPS35 subunit. This protein complex is internalized and later recycled into TGN. SorCS1c remains in complex with APP and retromer, which retains APP in TGN, and subsequently regulates its cleavage by BACE1 and γ-secretase. This way SorCS1 could control the physiological levels of secreted sAPPβ and Aβ. The abortion of SorCS1c-VPS35 interaction (left panel) enhances the APP anterograde trafficking causing an increased production and release of neurotoxic Aβ and sAPPβ. SorCS1 overexpression (OE; right panel) seems to strengthen the APP retention in TGN, thus significantly reducing the production and secretion of Aβ and sAPPβ, which has a neuroprotective effect against the formation of Aβ oligomers. Box E) SorCS1 is a substrate for PSEN1/2 and ADAM17, which attenuates its protein levels. However, molecular mechanisms involved in this regulation are unknown. Box F) SorCS1 sorts and recycles a number of synaptic receptors including Neurexin, AMPAR or Neuroligin at the postsynaptic side, by which it establishes the correct axon-to-dendrite polarization of synaptic proteins, processes critical for correct neurotransmission, connectivity, and synaptic plasticity