Objective
The pathological Ab peptide that accumulates in senile plaques in Alzheimer’s disease (AD) brains is derived from a precursor protein APP. Although etiology of AD is complex, genetic evidence shows that duplication of the APP gene locus leading to elevated levels of APP protein is sufficient to cause early-onset AD highlighting the importance of regulatory mechanisms. The events resulting in generation of Ab from APP are well characterized but the regulation of APP protein levels in cells is poorly understood. Previous studies suggest that a degradation pathway in the ER participates in the regulation of APP metabolism but the exact mechanism remains unknown. Recently, we have identified APP as a substrate for ER-associated degradation pathway (ERAD). Here, we will focus on characterization of the ERAD pathway of APP aiming at (1) identification of ERAD proteins that associate with APP, and (2) characterization of regulatory mechanisms that control ERAD of APP. We have identified an APP-binding protease HtrA2 that collaborates with the proteasome in ERAD of APP. Importantly, HtrA2-/- mice display a neurodegenerative phenotype and cells derived from these mice are increasingly susceptible to ER stress while secreting more Ab. Currently, there are no methods available for analyzing HtrA2 protease activity in cells and tissues. We will develop a fluorescence-based assay for HtrA2 activity to facilitate mechanistic studies linking HtrA2 to neurodegeneration. Modulation of APP metabolism in the early secretory pathway is an attractive therapeutic approach as it precedes other APP proteolytic processing events. Enhancement of ERAD could be used to downregulate APP metabolism and help the aging neurons in their battle against protein aggregation stress. Thus, the aims of this proposal are (1) to determine the role of ERAD as a catabolic pathway regulating APP levels and (2) to assess if changes in proteolytic activity of HtrA2 play a role in the pathogenesis of AD.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- natural sciences biological sciences biochemistry biomolecules proteins
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2007-4-3-IRG
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Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
00014 HELSINGIN YLIOPISTO
Finland
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.