A Centronuclear Myopathy - Dynamin 2 Mutation Impairs Autophagy in Mice
A Centronuclear Myopathy - Dynamin 2 Mutation Impairs Autophagy in Mice
复制标题
DOI：
10.1111/j.1600-0854.2012.01348.x
复制
发表时间：
2012-06-01
期刊：
影响因子：
4.5
通讯作者：
Bitoun, Marc
中科院分区：
文献类型：
--
作者：
Durieux, Anne-Cecile;Vassilopoulos, Stephane;Bitoun, Marc
动力蛋白2(Dynamin 2，Dnm2)通过其在不同的膜室形成囊泡的功能参与内吞作用和细胞内膜的转运。DNM2基因的杂合子(HTZ)突变导致显性中心核肌病或CharcotMarieTooth神经病。我们建立了一种表达最常见的人类突变的敲入Dnm2R465W小鼠模型，最近报告了HTZ小鼠进行性发展成肌病。我们在这里调查了纯合子(HMZ)小鼠新生儿死亡的原因。我们发现HMZ小鼠出生时体重减轻、低血糖、肝糖原含量增加和肝脏肿大，这与新生儿自噬缺陷是一致的。在HMZ胚胎成纤维细胞中进行的体外研究表明，在自溶酶体降解之前，自噬通量减少。我们发现饥饿的HMZ细胞有更多未成熟的自噬相关结构，可能是由于酸化的缺陷。我们的结果强调了DNM2在内体和自噬途径之间的串扰中的作用，并证明了DNM2依赖的膜运输在自噬中的新作用，这可能与DNM2相关的人类疾病有关。
Dynamin 2 (Dnm2) is involved in endocytosis and intracellular membrane trafficking through its function in vesicle formation from distinct membrane compartments. Heterozygous (HTZ) mutations in the DNM2 gene cause dominant centronuclear myopathy or CharcotMarieTooth neuropathy. We generated a knock-in Dnm2R465W mouse model expressing the most frequent human mutation and recently reported that HTZ mice progressively developed a myopathy. We investigated here the cause of neonatal lethality occurring in homozygous (HMZ) mice. We show that HMZ mice present at birth with a reduced body weight, hypoglycemia, increased liver glycogen content and hepatomegaly, in agreement with a defect in neonatal autophagy. In vitro studies performed in HMZ embryonic fibroblasts point out to a decrease in the autophagy flux prior to degradation at the autolysosome. We show that starved HMZ cells have a higher number of immature autophagy-related structures probably due to a defect of acidification. Our results highlight the role of Dnm2 in the cross talk between endosomal and autophagic pathways and evidence a new role of Dnm2-dependent membrane trafficking in autophagy which may be relevant in DNM2-related human diseases.