Journal
EMBO MOLECULAR MEDICINE
Volume 9, Issue 9, Pages 1294-1313Publisher
WILEY
DOI: 10.15252/emmm.201607315
Keywords
autophagy; MG132; PML-NBs; progerin; splicing
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Funding
- Institut National de la Sante et de la Recherche Medicale
- Aix-Marseille University
- A*Midex Foundation (Program VinTAGE)
- Association Francaise contre les Myopathies (AFM) [TRIM-RD 2016-2020]
- Investissement d'avenir French government [ANR-11-IDEX-001-02]
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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.
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