Alpha-synuclein oligomers activate NFAT proteins modulating synaptic homeostasis and apoptosis

Abstract

AbstractSoluble oligomeric forms of alpha-synuclein (aSyn-O) are believed to be one of the main toxic species in Parkinson’s 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 NFAT’s 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 synapticpunctaare 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 andSyn1gene regulation was demonstrated, enlarging our understanding of the pathways underpinnings synucleinopathies.