Deciphering the role of SorCS1 in neuronal transport

• Applicant: Privatdozent Dr. Guido Hermey
• Subject Area: Developmental Neurobiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534273114

SorCS1 has been associated with synaptopathies, including Alzheimer’s disease and autism. The transmembrane protein SorCS1 interacts with synaptic proteins and its ablation alters the surface expression of synaptic proteins. This suggests an important role in the localization of synaptic components. Although the proposed function as a neuronal sorting receptor is widely accepted, the mechanisms of how SorCS1 conveys sorting of other transmembrane proteins is incompletely understood and interacting cytosolic adaptors are poorly described.Alternative splicing increases molecular diversification and splice variants of synaptic proteins are thought to determine a cell- and synapse-specific code. Alternative splicing ads functional complexity to SorCS1 by resulting in receptors with identical extracellular and transmembrane moieties, but different cytoplasmic domains that contain distinct interaction motifs for various adaptor proteins. Therefore, the splice variants most likely mediate divergent functions. The relative contribution of the different SorCS1 splice variants to specific sorting paths and their specific interactions are not yet known. We aim to decipher if SorCS1 splice variants serve overlapping, complementary or separate functions resulting in the division of tasks or independent roles. Our preliminary studies show neuronal expression of three conserved SorCS1 variants with differential subcellular and somatodendritic localization. We observed interaction of the different SorCS1 variants with various cytosolic adaptors and divergent effects on neuronal surface expression by overexpression of distinct SorCS1 variants.In this application, we will test the hypothesis that the various SorCS1 variants are involved in targeting neuronal proteins in different ways. To this end, we propose to determine the neuronal surface proteome after ablation or overexpression of specific SorCS1 splice variants. In addition, we suggest to identify splice variant-specific protein-protein interaction maps. Additional experiments are required to determine whether SorCS1 variants convey surface localization of other proteins through differential interaction with specific postsynaptic adaptors that we have identified and to functionally characterize the interactions in detail.The planned comprehensive and systematic surveys will provide a rich compendium of interacting and sorted targets of SorCS1 variants. This proposal will integrate SorCS1 variants into neuronal sorting and postsynaptic interaction networks and define underlying regulatory mechanisms. The project aims to propose a general concept of how sorting receptors convey targeting of other transmembrane proteins. Therefore, the project will expand the knowledge on neuronal transport processes that, when dysfunctional, underlie neuronal diseases.

• DFG Programme: Research Grants