MG132 Induces Progerin Clearance and Improves Disease Phenotypes in HGPS-like Patients’ Cells

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

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Abstract

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 ∆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 (∆35 and ∆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.

Original languageEnglish
Article number610
Pages (from-to)1-35
Number of pages35
JournalCells
Volume11
Issue number4
DOIs
Publication statusPublished - 10 Feb 2022

Bibliographical note

Funding Information:
This work was supported by the French Muscular Dystrophy Association: AFM (?Modelisation and Therapeutic Approaches for Rare Diseases (MoThARD): 2021?2025? and ?TRIM-RD: 2016?2020? to A.D.S.G. and N.L.), the Institut National de la Sant? et de la Recherche M?dicale (INSERM): recurrent grants and Aix-Marseille University (AMU): recurrent grants.

Funding Information:
Funding: This work was supported by the French Muscular Dystrophy Association: AFM (“Mod-elisation and Therapeutic Approaches for Rare Diseases (MoThARD): 2021–2025” and “TRIM-RD: 2016–2020” to A.D.S.G. and N.L.), the Institut National de la Santé et de la Recherche Médicale (INSERM): recurrent grants and Aix-Marseille University (AMU): recurrent grants.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Autophagy
  • Inflammation
  • MAD-B
  • MG132
  • Prelamin A ∆35
  • Prelamin A ∆90
  • Progeria-like
  • Progerin

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