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.

Sbardella, D., Tundo, G.r., Cunsolo, V., Grasso, G., Cascella, R., Caputo, V., et al. (2020). Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE, 1866(7), 165793 [10.1016/j.bbadis.2020.165793].

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

Sbardella D.;Tundo G. R.;Cascella R.;Caputo V.;Ciaccio C.;Di Pierro D.;Campagnolo L.;Giardina E.;Curatolo P.;Galasso C.;Coletta M.;Graziani G.;Marini S.
2020-01-01

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
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10 - BIOCHIMICA
Settore BIOS-07/A - Biochimica
English
Con Impact Factor ISI
PAC1; PAC2; Proteasome; Rett syndrome; Skin primary fibroblasts; α-Ring
Sbardella, D., Tundo, G.r., Cunsolo, V., Grasso, G., Cascella, R., Caputo, V., et al. (2020). Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE, 1866(7), 165793 [10.1016/j.bbadis.2020.165793].
Sbardella, D; Tundo, Gr; Cunsolo, V; Grasso, G; Cascella, R; Caputo, V; Santoro, Am; Milardi, D; Pecorelli, A; Ciaccio, C; Di Pierro, D; Leoncini, S; ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/245871
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