The role of eEF1A in synapse function, maintenance, and synucleinopathy

ended

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 Fellow’s core scientific expertise, soft skills, and professional network to match her plans towards an independent academic research career.