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Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-04-08 , DOI: 10.1016/j.bbadis.2020.165793 Diego Sbardella 1 , Grazia Raffaella Tundo 2 , Vincenzo Cunsolo 3 , Giuseppe Grasso 3 , Raffaella Cascella 4 , Valerio Caputo 4 , Anna Maria Santoro 5 , Danilo Milardi 5 , Alessandra Pecorelli 6 , Chiara Ciaccio 2 , Donato Di Pierro 2 , Silvia Leoncini 7 , Luisa Campagnolo 8 , Virginia Pironi 8 , Francesco Oddone 1 , Priscilla Manni 9 , Salvatore Foti 3 , Emiliano Giardina 4 , Claudio De Felice 10 , Joussef Hayek 11 , Paolo Curatolo 8 , Cinzia Galasso 8 , Giuseppe Valacchi 6 , Massimiliano Coletta 2 , Grazia Graziani 12 , Stefano Marini 2
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-04-08 , DOI: 10.1016/j.bbadis.2020.165793 Diego Sbardella 1 , Grazia Raffaella Tundo 2 , Vincenzo Cunsolo 3 , Giuseppe Grasso 3 , Raffaella Cascella 4 , Valerio Caputo 4 , Anna Maria Santoro 5 , Danilo Milardi 5 , Alessandra Pecorelli 6 , Chiara Ciaccio 2 , Donato Di Pierro 2 , Silvia Leoncini 7 , Luisa Campagnolo 8 , Virginia Pironi 8 , Francesco Oddone 1 , Priscilla Manni 9 , Salvatore Foti 3 , Emiliano Giardina 4 , Claudio De Felice 10 , Joussef Hayek 11 , Paolo Curatolo 8 , Cinzia Galasso 8 , Giuseppe Valacchi 6 , Massimiliano Coletta 2 , Grazia Graziani 12 , Stefano Marini 2
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Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis.
中文翻译：
缺陷性蛋白酶体生物合成为皮肤成纤维细胞，该皮肤成纤维细胞从具有MeCP2无义突变的Rett综合征受试者中分离出来。
Rett综合征（RTT）是一种罕见的X连锁神经发育障碍，会影响约1：10000的活产。在> 95％的受试者中，RTT是由甲基CpG结合蛋白2（MECP2）基因突变引起的，该基因编码具有多效遗传/表观遗传活性的转录调节因子。强调RTT表型改变的分子机制在很大程度上是未知的，这削弱了在疾病发展过程中减轻体征和症状的治疗方法的开发。据报道，有缺陷的蛋白酶体生物发生进入两个皮肤原代成纤维细胞中，所述皮肤原代成纤维细胞从具有无义（早期截短）MeCP2突变（即R190fs和R255X）的RTT受试者中分离。蛋白酶体是泛素蛋白酶体系统（UPS）的蛋白水解机制，它是有丝分裂后细胞代谢的重要相关途径。分子，转录和蛋白质组学分析表明，MeCP2突变下调了一个蛋白酶体亚基α7以及两个分子伴侣PAC1和PAC2的表达，它们在蛋白酶体生物发生的最早步骤相互结合。此外，在MeCP2表达沉默后，这种分子改变在神经元样SH-SY5Y细胞中得以概括，这预示了这种转录调节因子在蛋白酶体生物发生中的一般意义。
更新日期：2020-04-20
中文翻译：
缺陷性蛋白酶体生物合成为皮肤成纤维细胞，该皮肤成纤维细胞从具有MeCP2无义突变的Rett综合征受试者中分离出来。
Rett综合征（RTT）是一种罕见的X连锁神经发育障碍，会影响约1：10000的活产。在> 95％的受试者中，RTT是由甲基CpG结合蛋白2（MECP2）基因突变引起的，该基因编码具有多效遗传/表观遗传活性的转录调节因子。强调RTT表型改变的分子机制在很大程度上是未知的，这削弱了在疾病发展过程中减轻体征和症状的治疗方法的开发。据报道，有缺陷的蛋白酶体生物发生进入两个皮肤原代成纤维细胞中，所述皮肤原代成纤维细胞从具有无义（早期截短）MeCP2突变（即R190fs和R255X）的RTT受试者中分离。蛋白酶体是泛素蛋白酶体系统（UPS）的蛋白水解机制，它是有丝分裂后细胞代谢的重要相关途径。分子，转录和蛋白质组学分析表明，MeCP2突变下调了一个蛋白酶体亚基α7以及两个分子伴侣PAC1和PAC2的表达，它们在蛋白酶体生物发生的最早步骤相互结合。此外，在MeCP2表达沉默后，这种分子改变在神经元样SH-SY5Y细胞中得以概括，这预示了这种转录调节因子在蛋白酶体生物发生中的一般意义。
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