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.

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with {MeCP}2 non-sense mutations / Sbardella, Diego; Raffaella Tundo, Grazia; Cunsolo, GAETANO VINCENZO; Grasso, Giuseppe; Cascella, Raffaella; Caputo, Valerio; Maria Santoro, Anna; Milardi, Danilo; Pecorelli, Alessandra; Ciaccio, Chiara; Di Pierro, Donato; Leoncini, Silvia; Campagnolo, Luisa; Pironi, Virginia; Oddone, Francesco; Manni, Priscilla; Foti, Salvatore; Giardina, Emiliano; De Felice, Claudio; Hayek, Joussef; Curatolo, Paolo; Galasso, Cinzia; Valacchi, Giuseppe; Coletta, Massimiliano; Graziani, Grazia; Marini, Stefano. - In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE. - ISSN 0925-4439. - 1866:7(2020). [10.1016/j.bbadis.2020.165793]

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with {MeCP}2 non-sense mutations

Vincenzo Cunsolo;Luisa Campagnolo;Priscilla Manni;Paolo Curatolo;Massimiliano Coletta;
2020

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
PAC1; PAC2; proteasome; rett syndrome; skin primary fibroblasts; α-Ring
01 Pubblicazione su rivista::01a Articolo in rivista
Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with {MeCP}2 non-sense mutations / Sbardella, Diego; Raffaella Tundo, Grazia; Cunsolo, GAETANO VINCENZO; Grasso, Giuseppe; Cascella, Raffaella; Caputo, Valerio; Maria Santoro, Anna; Milardi, Danilo; Pecorelli, Alessandra; Ciaccio, Chiara; Di Pierro, Donato; Leoncini, Silvia; Campagnolo, Luisa; Pironi, Virginia; Oddone, Francesco; Manni, Priscilla; Foti, Salvatore; Giardina, Emiliano; De Felice, Claudio; Hayek, Joussef; Curatolo, Paolo; Galasso, Cinzia; Valacchi, Giuseppe; Coletta, Massimiliano; Graziani, Grazia; Marini, Stefano. - In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE. - ISSN 0925-4439. - 1866:7(2020). [10.1016/j.bbadis.2020.165793]
File allegati a questo prodotto
File Dimensione Formato  
Sbardella_Defective proteasome_2020.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 2.11 MB
Formato Adobe PDF
2.11 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1669874
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 11
social impact