Project: Identification and structural characterization of the primordial cytotoxic conformers of the amyloidogenic cascade: Ideal prevention/diagnostic/therapeutic targets in neurodegeneration

In the coordinator’s laboratory, we have recently developed single-molecule force spectroscopy methods to detect conformational polymorphism in several representative neurotoxic proteins (NPs, e.g. polyQ, alpha-syn, Abeta, prion) including the first transformed conformers (missing link) that trigger the pathological neurodegenerative cascades. Our initial results show common features in NPs at the monomer level and validate the Conformational Change Hypothesis. The MisingLink consortium will refine this new methodology and combine it with established computational techniques such as Molecular Dynamics and Quantum Mechanics to provide further insight into the atomic level structure and energetics of these systems. Bulk structural techniques will be used also to characterize the starting critical conformations using specific strategies design in this project. First, we will further characterize our previously analyzed NP set in addition to Tau. We aim to characterize also new pathologically aggregating proteins to determine if they are amyloid in nature, if their monomers form highly mechanostable conformers and if the octapeptide QBP1 can block the coil-to-mechanostable transition for these novel proteins, as it does for most known amyloidogenic proteins. This knowledge will be used to study how other molecules affect the initial transition event. The knowledge gained will aid the development of innovative approaches for prevention, diagnosis and therapy.

Acronym MisingLink (Reference Number: JPND_CD_FP-688-059)
Duration 01/01/2015 - 01/01/2018
Project Topic Neurodegenerative disease
Website visit project website
Network JPND
Call A call for European research projects for cross-disease analysis of pathways related to neurodegenerative diseases

Project partner

Number Name Role Country
1 Agencia Estatal ConsejoSuperior de Investigaciones Científicas (CSIC) Coordinator Spain
2 Polish Academy of Sciences Partner Poland
3 University of Limerick Partner Ireland