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.
Mol Med. 2023 Aug 18;29(1):111. doi: 10.1186/s10020-023-00704-8.
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 influx, over activating downstream pathways leading to PD phenotype. Calcineurin (CN), a phosphatase regulated by Ca levels, activates NFAT transcription factors that are involved in the regulation of neuronal plasticity, growth, and survival.
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.
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.
可溶性寡聚体形式的α-突触核蛋白（aSyn-O）被认为是帕金森病（PD）导致神经元退行性变的主要毒性物质之一。aSyn-O 可以诱导 Ca2+内流，过度激活下游信号通路，导致 PD 表型。钙调神经磷酸酶（CN）是一种受 Ca2+水平调节的磷酸酶，它激活 NFAT 转录因子，参与神经元可塑性、生长和存活的调节。
在这里，我们使用细胞毒性和基因调控测定的组合，在 NFAT/CN 通路的经典抑制剂存在的情况下，研究 NFAT 在 aSyn-O 诱导的神经元退行性变中的作用。
aSyn-O 对神经元有毒性，导致细胞死亡、神经元分支丧失和突触蛋白减少，这些都可以通过 CN 抑制用环孢素 A 或 NFAT 特异性抑制剂 VIVIT 逆转。aSyn-O 诱导 NFAT 核转位和转录激活。我们发现 aSyn-O 调节参与维持突触的基因，突触素 1（Syn1）。用 aSyn-O 处理的细胞中 Syn1 mRNA 和蛋白以及突触小体明显减少，NFAT 抑制可逆转这一现象。
首次证明了 NFAT 在 aSyn-O 诱导的毒性和 Syn1 基因调控中的直接作用，扩大了我们对突触核蛋白病相关通路的理解。
