The alpha-synuclein oligomers activate nuclear factor of activated T-cell (NFAT) modulating synaptic homeostasis and apoptosis

Molecular Medicine

Research Article

Júlia Araújo de Freitas¹  Debora Foguel¹  Bruno K. Robbs²  Annekatrin König³  Patrícia Pires dos Santos³  Ricardo Sant’Anna⁴  Tiago Fleming Outeiro⁵ 

[1] Centro de Ciências da Saúde, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Bloco E sala 42, 21941-590, Rio de Janeiro, Brazil;Departamento de Ciência Básica, Instituto de Saúde de Nova Friburgo, Universidade Federal Fluminense, 28625-650, Nova Friburgo, RJ, Brazil;Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany;Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany;Centro de Ciências da Saúde, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Bloco E sala 42, 21941-590, Rio de Janeiro, Brazil;Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany;Max Planck Institute for Multidisciplinary Sciences, 37075, Göttingen, Germany;Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK;Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany;

关键词: Alpha-synuclein;    Synucleinopathies;    Parkinson’s disease;    NFAT;    Synapsin 1;    Synapses;   

DOI  :  10.1186/s10020-023-00704-8

 received in 2023-03-31, accepted in 2023-07-18,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSoluble 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.MethodsHere, using a combination of cell toxicity and gene regulation assays performed in the presence of classical inhibitors of the NFAT/CN pathway, we investigate NFAT’s role in neuronal degeneration induced by aSyn-O.ResultsaSyn-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.ConclusionsFor 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.

【 授权许可】

CC BY   
© The Feinstein Institute for Medical Research 2023

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