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Identification and characterization of new cytosolic ligands of Sortilin

Periodic Reporting for period 1 - SORT1LIG (Identification and characterization of new cytosolic ligands of Sortilin)

Reporting period: 2016-01-01 to 2017-12-31

Protein trafficking is crucial to maintain organelle function and cellular homeostasis, and is regulated by sorting receptors. Sortilin is a membrane receptor that sorts proteins to the predisposed cellular compartments. To accomplish this function Sortilin is endowed with an ectodomain that binds to a great variety of cargo proteins, and a cytosolic domain that recruits adaptor proteins which control its trafficking activities. In the last 15 years more than 20 cargo proteins of Sortilin have been identified leading to the discovery of key Sortilin functions related to lipoprotein metabolism, neurotrophic factor signaling and lysosomal trafficking. However, still little is known about the specific mechanisms that regulate Sortilin intracellular trafficking and function, since few cytosolic adaptors have been identified.
Based on this, the aim of the present project is to identify and characterize new cytosolic adaptors of Sortilin and shed light on these fundamental aspects Notably, elucidating the machinery and the molecular/regulatory mechanisms of protein trafficking is crucial to understand cellular physiology and pathology. In addition, since Sortilin is emerging as a major disease gene in cardiovascular, neurological, and neurodegenerative disorders, the results from the present project will provide new knowledge about the etiology of these complex diseases and propose novel therapeutic perspectives for their treatment.
The work perfomed during the duration of the action (3 months) was mainly focused on the expression analysis of Sortilin and of a candidate cytosolic adaptor in cell lines and in brain tissue homogenates. The results achieved allowed to identify two cell lines and two brain tissues co-expressing Sortilin and the canditate adaptor. These tools would be useful for future studies focused on the validation and characterization of their interaction.