title: Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts.
abstract: 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.
authors.affiliation: Department of Medicine, Epigenetics of skin Aging and Institute for Medical Engineering, Technische Universität München (TUM), Garching bei München, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Gabriel
authors.forename: Daniela
authors.initials: D
authors.lastname: Roedl
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Gordon
authors.forename: Karima
authors.initials: K
authors.lastname: Djabali
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004357:Drug Synergism; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D034904:Lamin Type A / Q000378:metabolism*; D013058:Mass Spectrometry; D010641:Phenotype; D011371:Progeria / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D013454:Sulfoxides
chemical_list: D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D034904:Lamin Type A; D020543:Proteome; D013454:Sulfoxides; C090764:prelamin A; D046988:Proteasome Endopeptidase Complex; C016766:sulforaphane
keywords: lamins; progeria; progerin; proteostasis; senescence; sulforaphane