EaSYFUN · The role of eEF1A in synapse function, maintenance, and synucleinopathy
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-06-01 → 2024-11-30
- EU contribution
- €235,853
- Participants
- 2
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
The role of eEF1A in synapse function, maintenance, and synucleinopathy
EaSYFUN explores early brain alterations in neurodegenerative diseases induced by synucleinopathy such as Parkinson's disease. These diseases induce progressive loss of motor control, tremor and rigidity as well as senile dementia. Synucleinopathies are associated with the abnormal accumulation of a protein called alpha-synuclein. This accumulation in the form of aggregates generates a loss of cells (neurons) and a loss of connections between neurons (synapses), but scientists still don’t fully understand the mechanisms driving this slow degeneration. The EaSYFUN project focuses on a protein called eukaryotic elongation factor 1 alpha (eEF1A), which is known for helping cells make other proteins by bringing the building blocks of the protein molecules to the site of synthesis. However, early findings suggest that eEF1A may play other roles in the brain, including in the response to misfolded proteins like alpha-synuclein. In mouse model of synucleinopathy, the host laboratory previously observed that eEF1A levels drop significantly when the first synapses display molecular changes in the disease progress (before any symptoms develop). The eEF1A is reduced specifically at synapses — the connections between neurons — suggesting that eEF1A loss might contribute to the development of synucleinopathies. EaSYFUN ambitions to clarify the involvement of eEF1A in normal function of synapse and how this function is then affected in pathology of synucleinopathy. By exploration of individual eEF1A possible functions in the cell, its involvement will be either eliminated or confirmed to participate to the disease triggering or progression. EaSYFUN includes several work packages (WPs) to investigate this hypothesis further.
Data: CORDIS, © European Union
Project objective
Synucleinopathies are neurodegenerative conditions characterized by an accumulation of the protein alpha-synuclein, including Parkinson's disease and dementia with Lewy bodies. A long asymptomatic phase precedes the onset of invalidating symptoms. Early diagnostics and treatments are hampered by an incomplete understanding of the pathophysiological mechanisms. The Host has recently identified the synaptic depletion of protein elongation factor 1A (eEF1A) at early stage of the disease. In EaSYFUN, the Fellow proposes to combine state of the art genome editing with transgenic murine disease model and human induced pluripotent stem cell derived neurons to unravel eEF1A function at synapses, characterize in depth its alterations in synucleinopathy, and question its pathophysiological role in the disease onset and progress. In Aim1 we shall provide a spatiotemporal map of eEF1A in neurons and its depletion in pathology. In Aim2 we will explore knock-down and rescue of eEF1A variants. We will test whether eEF1A depletion is necessary and sufficient to lead to all or some aspects of synucleinopathy. In Aim3 we will explore the functions of eEF1A variants at synapse (protein translation or degradation, regulation of synaptic vesicle cycle, spine structure) and the binding partners of eEF1A through proteomics. We will provide insights into the alterations of synaptic functions in synucleinopathy and the role of eEF1A. The applicant will benefit from established protocols by the Host and will bring new expertise to tackle eEF1A function at synapses with unprecedented resolution and to provide new therapeutic avenues for Synucleinopathy. EaSYFUN will benefit from an ongoing collaboration with Pr Jochen Herms (DZNE, Munich, Germany). The proposed work will expand the Fellows core scientific expertise, soft skills, and professional network to match her plans towards an independent academic research career.
Original text from CORDIS.
Participants
Links
- View on CORDIS
- DOI: 10.3030/101062581
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e518c4218f&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e518c42190&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5f583f4ac&appId=PPGMS
Data: CORDIS, © European Union