Open AccessMG 132‐induced progerin clearance is mediated by autophagy activation and splicing regulation
Author(s) -
Harhouri Karim,
Navarro Claire,
Depetris Danielle,
Mattei MarieGeneviève,
Nissan Xavier,
Cau Pierre,
De SandreGiovannoli Annachiara,
Lévy Nicolas
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201607315
Subject(s) - progeria , lmna , lamin , autophagy , biology , microbiology and biotechnology , downregulation and upregulation , cancer research , genetics , nucleus , apoptosis , gene
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 MG 132 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. MG 132 treatment improves cellular HGPS phenotypes. MG 132 injection in skeletal muscle of Lmna G609G/G609G mice locally reduces SRSF ‐1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG 132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS .