E3 泛素连接酶 TRIM17 和 TRIM41 通过调节 ZSCAN21 来调节 α-突触核蛋白的表达。
The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21.
机构信息
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
出版信息
Cell Rep. 2018 Nov 27;25(9):2484-2496.e9. doi: 10.1016/j.celrep.2018.11.002.
Although accumulating data indicate that increased α-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, SNCA, are largely unknown. Here, we describe a pathway regulating α-synuclein expression. Our data show that ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is an E3 ubiquitin ligase for ZSCAN21. In contrast, TRIM17 decreases the TRIM41-mediated degradation of ZSCAN21. Silencing of ZSCAN21 and TRIM17 consistently reduces SNCA expression, whereas TRIM41 knockdown increases it. The mRNA levels of TRIM17, ZSCAN21, and SNCA are simultaneously increased in the midbrains of mice following MPTP treatment. In addition, rare genetic variants in ZSCAN21, TRIM17, and TRIM41 genes occur in patients with familial forms of PD. Expression of variants in ZSCAN21 and TRIM41 genes results in the stabilization of the ZSCAN21 protein. Our data thus suggest that deregulation of the TRIM17/TRIM41/ZSCAN21 pathway may be involved in the pathogenesis of PD.
虽然越来越多的数据表明 α-突触核蛋白表达增加对帕金森病（PD）至关重要，但调节其基因 SNCA 转录的机制在很大程度上尚不清楚。在这里，我们描述了一个调节 α-突触核蛋白表达的途径。我们的数据表明，ZSCAN21 在神经元细胞中刺激 SNCA 转录，而 TRIM41 是 ZSCAN21 的 E3 泛素连接酶。相比之下，TRIM17 降低了 TRIM41 介导的 ZSCAN21 降解。沉默 ZSCAN21 和 TRIM17 一致降低 SNCA 的表达，而 TRIM41 的敲低则增加其表达。在 MPTP 处理后，小鼠的中脑中同时增加了 TRIM17、ZSCAN21 和 SNCA 的 mRNA 水平。此外，家族性 PD 患者的 ZSCAN21、TRIM17 和 TRIM41 基因中存在罕见的遗传变异。ZSCAN21 和 TRIM41 基因变异的表达导致 ZSCAN21 蛋白的稳定。因此，我们的数据表明，TRIM17/TRIM41/ZSCAN21 途径的失调可能与 PD 的发病机制有关。
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