MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation
Abstract Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A‐type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallma...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2017-09-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201607315 |
| _version_ | 1797279805472768000 |
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| author | Karim Harhouri Claire Navarro Danielle Depetris Marie‐Geneviève Mattei Xavier Nissan Pierre Cau Annachiara De Sandre‐Giovannoli Nicolas Lévy |
| author_facet | Karim Harhouri Claire Navarro Danielle Depetris Marie‐Geneviève Mattei Xavier Nissan Pierre Cau Annachiara De Sandre‐Giovannoli Nicolas Lévy |
| author_sort | Karim Harhouri |
| collection | DOAJ |
| description | Abstract Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A‐type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF‐1 and SRSF‐5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of LmnaG609G/G609G mice locally reduces SRSF‐1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS. |
| first_indexed | 2024-03-07T16:31:21Z |
| format | Article |
| id | doaj.art-3dccc1a6bece434b9ffa140170f11a46 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:31:21Z |
| publishDate | 2017-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-3dccc1a6bece434b9ffa140170f11a462024-03-03T10:20:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-09-01991294131310.15252/emmm.201607315MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulationKarim Harhouri0Claire Navarro1Danielle Depetris2Marie‐Geneviève Mattei3Xavier Nissan4Pierre Cau5Annachiara De Sandre‐Giovannoli6Nicolas Lévy7Aix Marseille Univ INSERM GMGF (Génétique Médicale et Génomique Fonctionnelle) Marseille FranceAix Marseille Univ INSERM GMGF (Génétique Médicale et Génomique Fonctionnelle) Marseille FranceAix Marseille Univ INSERM GMGF (Génétique Médicale et Génomique Fonctionnelle) Marseille FranceAix Marseille Univ INSERM GMGF (Génétique Médicale et Génomique Fonctionnelle) Marseille FranceCECS I‐STEM, Institut des cellules Souches pour le Traitement et l'Etude des maladies Monogéniques AFM Evry FranceAix Marseille Univ INSERM GMGF (Génétique Médicale et Génomique Fonctionnelle) Marseille FranceAix Marseille Univ INSERM GMGF (Génétique Médicale et Génomique Fonctionnelle) Marseille FranceAix Marseille Univ INSERM GMGF (Génétique Médicale et Génomique Fonctionnelle) Marseille FranceAbstract Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A‐type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF‐1 and SRSF‐5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of LmnaG609G/G609G mice locally reduces SRSF‐1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS.https://doi.org/10.15252/emmm.201607315autophagyMG132PML‐NBsprogerinsplicing |
| spellingShingle | Karim Harhouri Claire Navarro Danielle Depetris Marie‐Geneviève Mattei Xavier Nissan Pierre Cau Annachiara De Sandre‐Giovannoli Nicolas Lévy MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation EMBO Molecular Medicine autophagy MG132 PML‐NBs progerin splicing |
| title | MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation |
| title_full | MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation |
| title_fullStr | MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation |
| title_full_unstemmed | MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation |
| title_short | MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation |
| title_sort | mg132 induced progerin clearance is mediated by autophagy activation and splicing regulation |
| topic | autophagy MG132 PML‐NBs progerin splicing |
| url | https://doi.org/10.15252/emmm.201607315 |
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