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Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts

Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at...

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Autores principales: Gabriel, Diana, Roedl, Daniela, Gordon, Leslie B, Djabali, Karima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326906/
https://www.ncbi.nlm.nih.gov/pubmed/25510262
http://dx.doi.org/10.1111/acel.12300
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author Gabriel, Diana
Roedl, Daniela
Gordon, Leslie B
Djabali, Karima
author_facet Gabriel, Diana
Roedl, Daniela
Gordon, Leslie B
Djabali, Karima
author_sort Gabriel, Diana
collection PubMed
description Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS.
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spelling pubmed-43269062015-02-19 Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts Gabriel, Diana Roedl, Daniela Gordon, Leslie B Djabali, Karima Aging Cell Original Articles Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. BlackWell Publishing Ltd 2015-02 2014-12-16 /pmc/articles/PMC4326906/ /pubmed/25510262 http://dx.doi.org/10.1111/acel.12300 Text en © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Gabriel, Diana
Roedl, Daniela
Gordon, Leslie B
Djabali, Karima
Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
title Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
title_full Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
title_fullStr Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
title_full_unstemmed Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
title_short Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
title_sort sulforaphane enhances progerin clearance in hutchinson–gilford progeria fibroblasts
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326906/
https://www.ncbi.nlm.nih.gov/pubmed/25510262
http://dx.doi.org/10.1111/acel.12300
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