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

Project description

Structural analysis of the protein fibrils in the Huntington’s disease brain

The formation of protein fibrils in the brain is the most obvious sign of neurodegenerative diseases. The severity of Huntington’s disease (HD) symptoms and the onset age strongly correlate with an abnormally high number of glutamines in the huntingtin protein of affected individuals. Funded by the Marie Skłodowska-Curie Actions programme, the HUNTING-BrainFibrils project aims to obtain the atomic structures of soluble and insoluble fibrils extracted from the brains of patients with huntingtin gene mutations and map their in-situ interactions. The research will be conducted by an interdisciplinary research group, consisting of experts in HD pathology, structural biology, and interactomics. It will utilise state-of-the-art cryogenic electron microscopy, mass spectrometry-based proteomics, and immunological analysis.

Objective

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.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2021-PF-01

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Coordinator

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 173 847,36
Address
ROBERT ROSSLE STRASSE 10
13125 Berlin
Germany

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Region
Berlin Berlin Berlin
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Research Organisations
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Total cost

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