Project description
The role of lysosomes in neurodegeneration
Proteins are in a state of dynamic equilibrium, so they can adopt different conformational or functional states depending on factors like cellular conditions, interactions or environmental changes. Some proteins exist in cells in high concentration, which is crucial for cellular response to various stimuli. However, these proteins are more prone to losing their equilibrium and therefore more susceptible to misfolding or aggregation. The ERC-funded LEXSYN project focuses on the role of these metastable proteins in neuronal activity and synaptic plasticity. The hypothesis is that exocytotic lysosomes may serve as a surveillance mechanism in neurons, contributing to synaptic plasticity. The research team will also characterise the secretome of lysosomes in neurodegenerative diseases, uncovering fundamental mechanisms underlying protein turnover in neurons.
Objective
The extreme length and small caliber of neuronal processes entail complex local regulation of protein turnover. In light of the high metabolic demand and dynamic protein exchange imposed by synaptic neurotransmission, several surveillance mechanisms should be in place to sense protein damage that will otherwise cause synaptic dysfunction. However, it is still essentially unclear how local control of the metastable proteome, whose proteins have a high copy number and are crucial for synaptic function, is accomplished in dendrites to prevent formation of toxic aggregates. My previous work suggests that neuronal activity drives lysosomal fusion with the plasma membrane and exocytotic release of supersaturated, aggregation-prone proteins. The deposition of these proteins in the interstitial space likely feeds into the glymphatic system and cleaning routines associated with the enhanced circulation of cerebrospinal fluid during sleep. Intriguingly, I could show that, the concomitant release of lysosomal proteases enables growth of spine synapses suggesting that lysosomal exocytosis might serve both, protein removal and synaptic plasticity, whereas the latter might be an inevitable consequence of the necessity for local disposal of aggregation-prone proteins.
Building on my expertise in synapse biology and advanced imaging, the LEXSYN project aims to characterize the secretome of exocytotic lysosomes and to understand the consequences of dendritic lysosomal fusion for synaptic plasticity. I will decipher physiological signals regulating lysosomal exocytosis and investigate the pathological consequences of lysosomal fusion impairment, thereby assessing its relevance in neurodegenerative diseases. To achieve these ambitious goals, I will develop new tools for monitoring and manipulation of dendritic lysosomal exocytosis in vivo. I expect to reveal mechanisms of fundamental relevance for the control of the metastable proteome and its contribution to neurodegeneration.
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
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
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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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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.
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(opens in new window) ERC-2024-STG
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20251 Hamburg
Germany
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