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Author
Torné Cortada, Gerard
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Abstract
GPCRs (G protein-coupled receptors) are transmembrane receptors highly involved in multiple signalling pathways that affect numerous metabolic processes and cellular responses. Its basic structure consists of a transmembrane domain (TMD) made up of seven transmembrane alpha helices, three extracellular loops, three intercellular loops. In addition, they have a C-terminus and an N-terminus that can be large depending on the family and type of GPCR. In their extracellular part, GPCRs can undergo post-translational modifications such as glycosylation, while, in their intracellular part, they are bound to G proteins.
Parkinson's disease affects more than 160,000 people in Spain and more than 7 million worldwide. This is a neurodegenerative disease of the central nervous system that mainly impairs the locomotor system. Its origin comes from the degradation of dopamine-producing neurons in the region of the brain known as the substantia nigra, thus affecting the entire striatal dopaminergic pathway. In addition, at the end of this pathway, in the striatum, it has been observed that the mGlu5 and D1 receptors bind to form heteromers, a fact that has been related to the appearance of dyskinesia (involuntary tremors in the extremities). Dyskinesia has been associated with long-term treatment with levodopa, a dopamine precursor that is the most widely used drug for Parkinson's disease.
This project aims to design a method for specific and non-invasive fluorescent labelling of endogenously expressed receptors (mGlu5). Currently, there are various techniques for labelling GPCRs in artificial biological systems. This is achieved through the application of genetically modified proteins of interest or receptors overexpressed in cells. Because this labelling strategy is generally incompatible with its use in human samples or in clinical research, new technology needs to be developed to perform this type of assay on endogenous receptors present in primary cells or tissues, thus avoiding molecular biology or engineering. genetics. In order to carry out the objective of endogenous labelling, a ligand with a structure that allows, through a click reaction, to label the receptor fluorescently has been designed.
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