Ultrastructural analysis of mutant Huntingtin fibrils extracted from human brain tissue using high-resolution bioimaging and proteomics methods.

ongoing

The formation of protein fibrils in the brain is the most representative feature of neurodegenerative diseases. A detailed description of their structure and composition is essential to design new therapeutic approaches that allow patients to increase their life expectancy and quality of life. In Huntington’s disease (HD), the severity of the symptoms and the age of onset is strongly dependent on the number of glutamines above the threshold carried by the huntingtin protein of patients affected with this disorder. The two main objectives of this project are 1) to obtain atomic models of soluble and insoluble fibrils extracted directly from the brain tissues of individuals carrying extreme and moderate CAG repeats in the HTT gene and 2) mapping their in-situ interactions. Our approach will include state-of-the-art cryogenic electron microscopy, mass spectrometry-based proteomics and immunology. It will count on the participation of an interdisciplinary research group, comprising experts in HD pathology, structural biology and interactomics. The host institution counts with advanced facilities in image data analysis, cryo-EM and high-throughput proteomics that will be fully available. The host lab is an internationally recognised group that has more than 20 years of experience in carrying research focused on the molecular causes of HD in cell and animal models. It also has a strong background in mapping the interactions of the proteins that cause neurodegeneration in brain tissues. The host lab will take advantage of my expertise in assessing and validating protein-protein interactions through biochemical and biophysical methods. My visibility as a researcher will be greatly benefited by the extensive collaboration network of the host lab. The training and skills acquired during the execution of this project will expand and consolidate my research career and bring it to a very competitive point for taking a leading role as an independent researcher.