Neurodegenerative disorders such as Alzehimer´s or Parkinson´s affect millions of people in Europe and are linked to the misfolding and aggregation of proteins in the form of amyloid fibrils. The molecular pathways of amyloid aggregation are complex and poorly understood, and involve the population of oligomeric intermediates before fibrils form. Little is known about the role in vivo of amyloid intermediates, despite generally recognized as the major neurotoxic agents. The challenge of this project is to bridge the gap between structural and functional studies of amyloid intermediates, and to rationalize the role of protein-associated factors in amyloid toxicity. I intend to provide new experimental evidence into the causes of conformation-dependent neurotoxicity for the protein alpha-synuclein, the amyloid culprit of Parkinson’s disease. I will identify cellular factors associated with amyloid intermediates by employing mass spectrometry techniques. A protein interaction map for such amyloid species will be created based on the proteins identified. This protein network will provide a pathological atlas of the cellular pathways affected upon amyloid formation. Selected protein targets of the oligomeric intermediates will be characterized structurally, with the aim of identifying structural determinants of amyloid toxicity, the so-called amyloid hot spots. State of the art biophysical methodologies, such as NMR, fluorescence spectroscopy and microscopy will be employed, all of them available at the host institution. Finally, computational modeling of protein-protein interactions will support the experimental work, another major expertise of the host laboratory. It is foreseen that such amyloid hot spots will naturally become targets for therapeutic intervention. Accordingly, the present proposal will have impact on both basic and translational research in Parkinson’s disease.
Field of science
- /medical and health sciences/basic medicine/neurology/parkinson
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins/proteomics
- /natural sciences/chemical sciences/analytical chemistry/mass spectrometry
Call for proposal
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