Lysosomal exocytosis of metastable proteins to control synaptic functioncore
LEXSYN · Horizon Europe grant · 2025-04-01–2030-03-31
EC contribution
Total cost
Beneficiaries
About the data
Source: CORDIS (official EU open data), Horizon Europe. Framework HORIZON · call ERC-2024-STG · scheme HORIZON-ERC · topic ERC-2024-STG. CORDIS record →
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.
Beneficiaries (1)
| Organisation | Country | Role | EC contribution | SME |
|---|---|---|---|---|
| UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF | DE | coordinator | €2,037,356 |
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