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Novel tools for real time monitoring and quantification of protein aggregation in Parkinson s disease and related neurodegenerative disorders

Objective

To understand the molecular basis of any biological process, it is critical that one is not only able to visualize and monitor molecular events that underlie this process, but also to possess the tools to manipulate these events in a spatial and temporal fashion both in and out of the cell. The overall objective of this proposal is to apply chemical biology approaches to allow real time monitoring of protein aggregation and to dissect the role of specific disease-associated post-translational modifications, phosphorylation, nitration, and truncation on the structure, aggregation, and biochemical properties of monomeric a-syn in health and disease. To achieve these goals, we plan to use a combination of organic chemistry, molecular biology, proteomics, protein engineering, and semisynthetic strategies to facilitate site-specific introduction of post-translational modifications that can be masked and activated in a controllable manner, both inside and outside living cells. Modified synthetic ±-syn will be introduced into primary neurons and cellular models of synucleinopathies and the consequences of masking or activating specific modifications will be assessed using biochemical, immunofluorescence, and live imaging techniques (Specific Aim 1). The absence of specific molecular probes that allow in vivo monitoring and quantitative measurement of toxic misfolded and aggregation intermediates represents a major impediment to understanding the relationship among protein misfolding, post-translational modification, protein aggregation, neurodegeneration, and cell death in PD and other neurodegenerative disorders. To address this challenge, we plan to develop and characterize novel antibodies that target different species along the amyloid formation pathway of ±-syn (Specific Aim 2).

Field of science

  • /natural sciences/chemical sciences/organic chemistry
  • /natural sciences/biological sciences/molecular biology
  • /medical and health sciences/basic medicine/neurology/parkinson
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/proteomics

Call for proposal

ERC-2009-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Address
Batiment Ce 3316 Station 1
1015 Lausanne
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 495 400
Principal investigator
Hilal Lashuel (Prof.)
Administrative Contact
Caroline Vandevyver (Ms.)

Beneficiaries (1)

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Switzerland
EU contribution
€ 1 495 400
Address
Batiment Ce 3316 Station 1
1015 Lausanne
Activity type
Higher or Secondary Education Establishments
Principal investigator
Hilal Lashuel (Prof.)
Administrative Contact
Caroline Vandevyver (Ms.)