MG 132‐induced progerin clearance is mediated by autophagy activation and splicing regulation

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 . image Progerin is a toxic protein that accumulates in the nuclei of Progeria patients' cells, sequestered in abnormal PML ‐ NB s. The proteasome inhibitor MG 132 is shown to degrade progerin by activating autophagy and transcriptional inhibition through SRSF ‐1 and SRSF ‐5 splicing regulation. Ubiquitinylated progerin is sequestered into abnormal ProMyelocytic Leukemia Nuclear Bodies ( PML ‐ NB s). Progerin reduction is based on MG 132 dual action: autophagy activation and splicing regulation. MG132 in vitro treatment rescues most of the biological hallmarks of progeria. MG 132 local treatment efficiently reduces progerin levels in vivo , in the Lmna G609G/G609G mouse model. The powerful and dual activities of MG 132 make it a promising drug towards a future and safe therapeutic development for Progeria and related Prelamin‐A processing defective diseases.