Format

Send to

Choose Destination
EMBO Mol Med. 2017 Sep;9(9):1294-1313. doi: 10.15252/emmm.201607315.

MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation.

Author information

1
Aix Marseille Univ, INSERM, GMGF (Génétique Médicale et Génomique Fonctionnelle), Marseille, France.
2
CECS, I-STEM, Institut des cellules Souches pour le Traitement et l'Etude des maladies Monogéniques, AFM, Evry, France.
3
AP-HM, Hôpital la Timone, Service de Biologie Cellulaire, Marseille, France.
4
AP-HM, Hôpital la Timone, Département de Génétique Médicale, Marseille, France.
5
Aix Marseille Univ, INSERM, GMGF (Génétique Médicale et Génomique Fonctionnelle), Marseille, France nicolas.levy@univ-amu.fr.

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.

KEYWORDS:

MG132; PML‐NBs; autophagy; progerin; splicing

PMID:
28674081
PMCID:
PMC5582415
DOI:
10.15252/emmm.201607315
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center