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bioRxiv · 10.1101/2023.02.21.529374

Alpha-synuclein oligomers activate nuclear factor of activated T-cells (NFAT) modulating apoptosis and synaptic homeostasis

Sant'anna, R.·Robbs, B. K.·Araujo, J. F.·dos Santos, P. P.·Konig, A.·Outeiro, T. F.·Foguel, D.
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Abstract

Soluble oligomeric forms of alpha-synuclein (aSyn-O) are believed to be one of the main toxic species in Parkinsons disease (PD) leading to degeneration. aSyn-O can induce Ca2+ influx, over activating downstream pathways leading to PD phenotype. Calcineurin (CN), a phosphatase regulated by Ca2+ levels, activates NFAT transcription factors that are involved in the regulation of neuronal plasticity, growth and survival. Here, we investigate NFATs role in neuronal degeneration induced by aSyn-O. aSyn-O are toxic to neurons leading to cell death, loss of neuron ramification and reduction of synaptic proteins which are reversed by CN inhibition with ciclosporin-A or VIVIT, a NFAT specific inhibitor. aSyn-O induce NFAT nuclear translocation and transactivation. We found that aSyn-O modulates the gene involved in the maintenance of synapses, synapsin 1 (Syn 1). Syn1 mRNA and protein and synaptic puncta are drastically reduced in cells treated with aSyn-O which are reversed by NFAT inhibition. For the first time a direct role of NFAT in aSyn-O-induced toxicity and Syn1 gene regulation was demonstrated, enlarging our understanding of the pathways underpinnings synucleinopathies.

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Sant'anna, R., Robbs, B. K., Araujo, J. F., dos Santos, P. P., Konig, A., Outeiro, T. F., Foguel, D.. 2023-02-22. Alpha-synuclein oligomers activate nuclear factor of activated T-cells (NFAT) modulating apoptosis and synaptic homeostasis. https://doi.org/10.1101/2023.02.21.529374

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