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Proteasomal degradation of toxic intracellular amyloid-beta protein by nanobody-enabled proximity to ubiquitin ligase

Project description

An innovative treatment for Alzheimer’s disease

In Alzheimer’s disease (AD), production of the amyloid-beta (Aβ) protein from the Aβ precursor protein exceeds its clearance rate, leading to the aberrant accumulation of the former into amyloid plaques. These toxic forms of Aβ induce neuroinflammation and neurodegeneration, leading to the loss of cognitive functions in AD patients. The EU-funded Protambbody project proposes to guide Aβ peptide clearance by the selective proteosome degradation system of the cell. This novel approach presents a promising disease-modifying strategy for AD and offers an alternative to current, unsatisfactory efforts promoting immunisation against the Aβ peptide.

Objective

The amyloid-beta (A) protein arises from the sequential proteolytic cleavage of A precursor protein (APP). The accumulation of A oligomers has been regarded as the causal factor of Alzheimers disease (AD). Basal metabolic production of the A peptide is typical in healthy people, and its production rate is normally lower than its rate of clearance. In AD, the uncontrolled accumulation of toxic forms of A stemming from problems in its clearance and degradation results in memory loss, chronic neuroinflammation and neurodegeneration. AD is a leading cause of disability and death both in Europe and the world, and currently has no cure or clinically-proven disease-modifying therapies.

There are over 10 million new cases of dementia each year worldwide (up to 80% of which are due to AD), implying one new case every 3.2 seconds. In Europe, about 10 million people currently suffer from this disease and about 50 million in the world; with these estimates projected to double by 2050. Thus, the identification of novel disease-modifying therapies has become very critical to eradicating AD from Europe and the world. My project proposes a radically novel approach in the AD field of utilizing the bodys cellular waste disposal system to selectively degrade A peptide, the causative agent of AD. This is in sharp contrast to the current approach of immunization against the A peptide, which has repeatedly failed to yield any cure or disease-modifying therapies for AD.

This project will aim to identify the specific cytotoxic A peptides responsible for neuroinflammation and neurodegeneration in human induced pluripotent stem cells and target these peptides for degradation by the ubiquitin proteasome system. Emphasis will be on the cytotoxic A peptides of intracellular origin as emerging targets in AD. This research will be conducted at the University of Helsinki, Finland, followed by a non-academic placement at Roche Diagnostics GmbH.

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Topic(s)

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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

HELSINGIN YLIOPISTO
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.

€ 269 418,00
Address
FABIANINKATU 33
00014 HELSINGIN YLIOPISTO
Finland

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Activity type
Higher or Secondary Education Establishments
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Total cost

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