MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation.
MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation.
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DOI：
10.15252/emmm.201607315
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发表时间：
2017-09
影响因子：
11.1
通讯作者：
Lévy N
中科院分区：
文献类型：
--
作者：
Harhouri K;Navarro C;Depetris D;Mattei MG;Nissan X;Cau P;De Sandre-Giovannoli A;Lévy N
Hutchinson-Gilford早衰综合征（HGPS）是一种致命的过早和加速老化疾病，由编码A型核纤层蛋白的LMNA中的从头点突变引起。早老蛋白是一种由异常剪接产生的截短且有毒的前层蛋白A，在HGPS细胞的细胞核中积累，并且是该疾病的标志。在正常衰老过程中也会产生少量的早老蛋白。我们发现，早老蛋白被隔离到异常形状的早幼粒细胞核体，确定为新的生物标志物在晚代HGPS细胞系。我们发现，蛋白酶体抑制剂MG 132通过巨自噬诱导早老蛋白降解，并通过下调SRSF-1和SRSF-5积累，控制前层蛋白A mRNA异常剪接，强烈减少早老蛋白的产生。MG 132治疗改善细胞HGPS表型。在Lmna G609 G/G609 G小鼠的骨骼肌中注射MG 132局部降低SRSF-1表达和早老蛋白水平。总之，我们证明了基于MG 132双重作用的早老蛋白减少，并揭示了一类有前途的分子对HGPS儿童的潜在治疗。
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.