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 Lmna G609G/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.
Highlights
Hutchinson–Gilford progeria syndrome (HGPS; OMIM #176670) is a rare genetic disorder, which affects one in 4–8 million children with features of early and accelerated segmental aging
At late passages, the number of classical Promyelocytic leukemia nuclear bodies (PML-NBs) decreased (Control: 20 Æ 6 vs. HGPS: 8 Æ 4) and the number of aberrant ring-like and thread-like PML-NBs appeared and continuously increased in HGPS nuclei, while abnormal PML-NBs were very rarely detected in control fibroblasts, even in more aged cultures (Fig EV1B), suggesting that these ring-like and thread-like PML-NBs may be considered as novel disease biomarkers in late passage HGPS cell lines
The present study focused on the dynamics of progerin localization and the putative involvement of the three main protein degradation systems, in its clearance, which is overtly deficient in HGPS cells
Summary
Hutchinson–Gilford progeria syndrome (HGPS; OMIM #176670) is a rare genetic disorder, which affects one in 4–8 million children with features of early and accelerated segmental aging. These include growth retardation, thin skin, loss of subcutaneous fat, alopecia, osteoporosis, and myocardial infarction, which is the most frequent cause of death. HGPS patients die at the mean age of 14.6 years (Gordon et al, 2014) This accelerated aging disease is caused by a de novo synonymous point mutation (c.1824C>T, p.G608G) in exon 11 of the LMNA gene encoding A-type lamins (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003). Promyelocytic leukemia nuclear bodies (PML-NBs) are discrete nuclear speckles tightly associated with the nuclear matrix (Ascoli & Maul, 1991) and implicated in cellular senescence (Ferbeyre, 2002), whose nuclear arrangement was shown to be influenced by A-type lamin deficiency (Stixova et al, 2012)
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