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

Autor: Sant'Anna R; 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, Rio de Janeiro, 21941-590, Brazil., Robbs BK; Departamento de Ciência Básica, Instituto de Saúde de Nova Friburgo, Universidade Federal Fluminense, Nova Friburgo, RJ, 28625-650, Brazil., de Freitas JA; Centro de Ciências da Saúde, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Bloco E sala 42, Rio de Janeiro, 21941-590, Brazil., Dos Santos PP; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany., König A; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany., Outeiro TF; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany. touteir@gwdg.de.; Max Planck Institute for Multidisciplinary Sciences, 37075, Göttingen, Germany. touteir@gwdg.de.; Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. touteir@gwdg.de.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany. touteir@gwdg.de., Foguel D; Centro de Ciências da Saúde, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Bloco E sala 42, Rio de Janeiro, 21941-590, Brazil. foguel@bioqmed.ufrj.br.
Jazyk: angličtina
Zdroj: Molecular medicine (Cambridge, Mass.) [Mol Med] 2023 Aug 18; Vol. 29 (1), pp. 111. Date of Electronic Publication: 2023 Aug 18.
DOI: 10.1186/s10020-023-00704-8
Abstrakt: Background: Soluble 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 Ca 2+ influx, over activating downstream pathways leading to PD phenotype. Calcineurin (CN), a phosphatase regulated by Ca 2+ levels, activates NFAT transcription factors that are involved in the regulation of neuronal plasticity, growth, and survival.
Methods: Here, 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.
Results: 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.
Conclusions: 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.
(© 2023. The Feinstein Institute for Medical Research.)
Databáze: MEDLINE
Externí odkaz: