Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations: Biochimica et Biophysica Acta - Molecular Basis of Disease

D. Sbardella, G.R. Tundo, V. Cunsolo, G. Grasso, R. Cascella, V. Caputo, A.M. Santoro, D. Milardi, A. Pecorelli, C. Ciaccio, D. Di Pierro, S. Leoncini, L. Campagnolo, V. Pironi, F. Oddone, P. Manni, S. Foti, E. Giardina, C. De Felice, J. HayekP. Curatolo, C. Galasso, G. Valacchi, M. Coletta, G. Graziani, S. Marini

Research output: Contribution to journalArticlepeer-review

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. © 2020 Elsevier B.V.
Original languageEnglish
JournalBiochim. Biophys. Acta Mol. Basis Dis.
Volume1866
Issue number7
DOIs
Publication statusPublished - 2020

Keywords

  • PAC1
  • PAC2
  • Proteasome
  • Rett syndrome
  • Skin primary fibroblasts
  • α-Ring
  • dual specificity phosphatase 2
  • methyl CpG binding protein 2
  • proteasome
  • small interfering RNA
  • vasoactive intestinal polypeptide receptor 2
  • MECP2 protein, human
  • ubiquitin
  • allosterism
  • Article
  • biogenesis
  • controlled study
  • down regulation
  • gel electrophoresis
  • human
  • human cell
  • nonsense mutation
  • priority journal
  • protein binding
  • protein degradation
  • protein expression
  • real time polymerase chain reaction
  • SH-SY5Y cell line
  • skin fibroblast
  • transcription regulation
  • fibroblast
  • gene expression regulation
  • genetics
  • mental disease
  • metabolism
  • pathology
  • primary cell culture
  • skin
  • stop codon
  • X chromosome linked disorder
  • Codon, Nonsense
  • Dual Specificity Phosphatase 2
  • Fibroblasts
  • Gene Expression Regulation
  • Genetic Diseases, X-Linked
  • Humans
  • Methyl-CpG-Binding Protein 2
  • Neurodevelopmental Disorders
  • Primary Cell Culture
  • Proteasome Endopeptidase Complex
  • Proteolysis
  • Rett Syndrome
  • Skin
  • Ubiquitin

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