Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations.

Abstract

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.

• Authors: Diego Sbardella, Grazia Raffaella Tundo, Vincenzo Cunsolo, Giuseppe Grasso, Raffaella Cascella, Valerio Caputo, Anna Maria Santoro, Danilo Milardi, Alessandra Pecorelli, Chiara Ciaccio, Donato Di Pierro, Silvia Leoncini, Luisa Campagnolo, Virginia Pironi, Francesco Oddone, Priscilla Manni, Salvatore Foti, Emiliano Giardina, Claudio De Felice, Joussef Hayek, Paolo Curatolo, Cinzia Galasso, Giuseppe Valacchi, Massimiliano Coletta, Grazia Graziani, Stefano Marini
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1866 Issue 7 Pg. 165793 (07 01 2020) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 32275946 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Codon, Nonsense
• MECP2 protein, human
• Methyl-CpG-Binding Protein 2
• Ubiquitin
• Dual Specificity Phosphatase 2
• Proteasome Endopeptidase Complex

Topics

• Codon, Nonsense (genetics)
• Dual Specificity Phosphatase 2 (genetics)
• Fibroblasts (metabolism)
• Gene Expression Regulation
• Genetic Diseases, X-Linked (genetics, pathology)
• Humans
• Methyl-CpG-Binding Protein 2 (genetics)
• Neurodevelopmental Disorders (genetics, pathology)
• Primary Cell Culture
• Proteasome Endopeptidase Complex (genetics)
• Proteolysis
• Rett Syndrome (genetics, pathology)
• Skin (metabolism, pathology)
• Ubiquitin (genetics)