| Autor: |
Ricardo Sant’Anna, Bruno K. Robbs, Júlia Araújo de Freitas, Patrícia Pires dos Santos, Annekatrin König, Tiago Fleming Outeiro, Debora Foguel |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecular Medicine, Vol 29, Iss 1, Pp 1-16 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1528-3658 |
| DOI: |
10.1186/s10020-023-00704-8 |
| Popis: |
Abstract 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 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. 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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