1. MG132 Induces Progerin Clearance and Improves Disease Phenotypes in HGPS-like Patients' Cells
- Author
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Karim, Harhouri, Pierre, Cau, Frank, Casey, Koffi Mawuse, Guedenon, Yassamine, Doubaj, Lionel, Van Maldergem, Gerardo, Mejia-Baltodano, Catherine, Bartoli, Annachiara, De Sandre-Giovannoli, Nicolas, Lévy, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ProGeLife [Marseille], Royal Belfast Hospital for Sick Children, Centre Hospitalier Universitaire Sylvanus Olympio [Lomé, Togo], Institut National d’Hygiène [Rabat, Morocco], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Cell Nucleus ,congenital, hereditary, and neonatal diseases and abnormalities ,MG132 ,autophagy ,integumentary system ,Leupeptins ,prelamin A Delta 90 ,[SDV]Life Sciences [q-bio] ,nutritional and metabolic diseases ,Phenotype ,Progeria ,inflammation ,MAD-B ,progerin ,progeria-like ,Humans ,prelamin A Delta 35 - Abstract
International audience; Progeroid syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS), are premature and accelerated aging diseases, characterized by clinical features mimicking physiological aging. Most classical HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type lamins. This mutation activates a cryptic splice site, leading to the production of a truncated prelamin A, called prelamin A increment 50 or progerin, that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry other LMNA mutations and are named ``HGPS-like `` patients. They produce progerin and/or other truncated prelamin A isoforms ( increment 35 and increment 90). We previously found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patients' cells other than those previously described in classical HGPS. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like or classical HGPS.
- Published
- 2022