The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21
The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21
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DOI：
10.1016/j.celrep.2018.11.002
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发表时间：
2018-11-27
期刊：
影响因子：
8.8
通讯作者：
Desagher, Solange
中科院分区：
文献类型：
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作者：
Lassot, Irena;Mora, Stephan;Desagher, Solange
尽管越来越多的数据表明，α-突触核蛋白表达增加对于帕金森病 (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，我们描述了调节 α-突触核蛋白表达的途径。我们的数据显示 ZSCAN21 刺激神经元细胞中的 SNCA 转录，并且 TRIM41 是 ZSCAN21 的 E3 泛素连接酶。相反，TRIM17 减少 TRIM41 介导的 ZSCAN21 降解。 ZSCAN21 和 TRIM17 的沉默会持续降低 SNCA 的表达，而 TRIM41 敲除则会增加 SNCA 的表达。 MPTP 治疗后，小鼠中脑中 TRIM17、ZSCAN21 和 SNCA 的 mRNA 水平同时增加。此外，ZSCAN21、TRIM17 和 TRIM41 基因的罕见遗传变异发生在家族性 PD 患者中。 ZSCAN21 和 TRIM41 基因中变体的表达导致 ZSCAN21 蛋白的稳定。因此，我们的数据表明 TRIM17/TRIM41/ZSCAN21 通路的失调可能与 PD 的发病机制有关。
Although accumulating data indicate that increased alpha-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 alpha-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.