Project description
How the brain manages damaged proteins at synapses
Synapses experience oxidative stress due to mitochondrial activity that can damage long-lived neuronal proteins. The mechanisms used by synapses to manage this risk are not well understood. However, it is essential to identify which proteins are affected and how they are cleared via signals such as ubiquitin. This knowledge is crucial for recognising the restorative effects of sleep. The ERC-funded SYNDAM project aims to investigate how the brain detects and clears damaged proteins at synapses. Specifically, it will identify regulators of protein damage and explore the role of sleep in this process. The project will analyse synaptic activity and sleep behaviour in mice to uncover how damaged proteins are removed before causing cellular stress and neuroinflammation.
Objective
SYNDAM investigates how the brain detects and clears damaged proteins at the primary loci for information transfer and storage— synapses.
The synapse expresses many proteins that are mutated or dysregulated in major brain disorders. The information transfer rate at synapses is high and, as a result, synapses are continuously exposed to oxidative challenges that arise from local mitochondrial respiration and oxidase activity. This puts synaptic proteins at risk. This risk is exacerbated by the long lifetimes of neuronal proteins, which prolong their exposure to environmental assaults. It is unclear how this apparent risk is mitigated by protein quality control at synapses— a vital process for brain waste clearance and synaptic homeostasis e.g. during sleep. In this context, we face a fundamental knowledge gap: we do not even know which synaptic proteins are targets of oxidative damage, let alone how such damage may trigger protein clearance via key cellular degradation signals such as ubiquitin. This elusive damage-control mechanism is critical for the restorative function of sleep.
To address these knowledge gaps, SYNDAM will
(1) identify the synaptic ubiquitin regulators that can detect protein oxidative damage
(2) visualize the activity-dependent synaptic protein oxidative damage and ubiquitylation in situ
(3) investigate sleep-regulated detection and clearance of protein oxidative damage through ubiquitin
To achieve these goals, we will combine subcellular oxidized and ubiquitylated proteomics, DNA PAINT-based single-molecule localization, chemogenetic induction of synaptic oxidative damage, in situ detection of protein modifications, functional imaging, synaptic activity manipulations, electrophysiology, and sleep behaviour in mice.
SYNDAM will elucidate a critical surveillance mechanism for removing damaged proteins before protein toxicity activates cellular stress responses that may lead to neuroinflammation and degeneration.
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 biochemistry biomolecules proteins proteomics
- medical and health sciences basic medicine physiology homeostasis
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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)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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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.
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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.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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(opens in new window) ERC-2025-STG
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8000 Aarhus C
Denmark
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