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

doi:10.3390/cells11040610

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

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

160 Downloads (Pure)

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 language	English
Article number	610
Pages (from-to)	1-35
Number of pages	35
Journal	Cells
Volume	11
Issue number	4
DOIs	https://doi.org/10.3390/cells11040610
Publication status	Published (in print/issue) - 10 Feb 2022

Bibliographical note

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.

Funding

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: 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

Access to Document

10.3390/cells11040610Licence: CC BY

Published_VersionFinal published version, 8.86 MBLicence: CC BY

Cite this

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title = "MG132 Induces Progerin Clearance and Improves Disease Phenotypes in HGPS-like Patients{\textquoteright} Cells",

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{\textquoteright} 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.",

keywords = "Autophagy, Inflammation, MAD-B, MG132, Prelamin A ∆35, Prelamin A ∆90, Progeria-like, Progerin",

author = "Karim Harhouri and Pierre Cau and Frank Casey and Guedenon, \{Koffi Mawuse\} and Yassamine Doubaj and Maldergem, \{Lionel Van\} and Gerardo Mejia-Baltodano and Catherine Bartoli and \{De Sandre-Giovannoli\}, Annachiara and Nicolas L{\'e}vy",

note = "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 Sant{\'e} et de la Recherche M{\'e}dicale (INSERM): recurrent grants and Aix-Marseille University (AMU): recurrent grants. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

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day = "10",

doi = "10.3390/cells11040610",

language = "English",

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AU - Harhouri, Karim

AU - Cau, Pierre

AU - Casey, Frank

AU - Guedenon, Koffi Mawuse

AU - Doubaj, Yassamine

AU - Maldergem, Lionel Van

AU - Mejia-Baltodano, Gerardo

AU - Bartoli, Catherine

AU - De Sandre-Giovannoli, Annachiara

AU - Lévy, Nicolas

N1 - 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.

PY - 2022/2/10

Y1 - 2022/2/10

N2 - 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.

AB - 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.

KW - Autophagy

KW - Inflammation

KW - MAD-B

KW - MG132

KW - Prelamin A ∆35

KW - Prelamin A ∆90

KW - Progeria-like

KW - Progerin

UR - https://www.scopus.com/pages/publications/85124248477

U2 - 10.3390/cells11040610

DO - 10.3390/cells11040610

M3 - Article

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AN - SCOPUS:85124248477

SN - 2073-4409

VL - 11

SP - 1

EP - 35

JO - Cells

JF - Cells

IS - 4

M1 - 610

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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