Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.
Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.
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无脑畸形是一种由于神经元迁移缺陷而导致的破坏性神经疾病。Lis1(或PAFAH1B1)基因被鉴定为无脑畸形患者的突变基因，并被发现调节细胞质动力蛋白的功能和定位。在这里，我们发现，超过一半的Lis1蛋白通过依赖于Calain的蛋白分解而被降解，抑制或敲除Calain蛋白可以保护Lis1蛋白不被降解，导致Lis1+/−小鼠胚胎成纤维细胞中Lis1水平的升高，从而挽救细胞质动力蛋白、线粒体和β-COP阳性囊泡的异常分布。我们还发现，钙蛋白酶抑制剂可以改善Lis1+/−小脑颗粒神经元的迁移。孕鼠Lis1+/−经腹注射ALLN可挽救Lis1+/−子代的神经细胞死亡和神经元迁移缺陷。此外，在子宫中，通过shRNA敲除Calain可以挽救Lis1+/−小鼠大脑皮质分层的缺陷。因此，抑制钙蛋白酶是一种潜在的治疗无脑畸形的干预措施。
Lissencephaly is a devastating neurological disorder due to defective neuronal migration. LIS1 (or PAFAH1B1) was identified as the gene mutated in lissencephaly patients, and was found to regulate cytoplasmic dynein function and localization. Here, we show that more than half of LIS1 is degraded via calpain-dependent proteolysis, and that inhibition or knockdown of calpains protects LIS1 from proteolysis, resulting in the augmentation of LIS1 levels in Lis1+/− mouse embryonic fibroblast (MEF) cells, which leads to rescue of the aberrant distribution of cytoplasmic dynein, mitochondria and β-COP positive vesicles. We also show that calpain inhibitors improve neuronal migration of Lis1+/− cerebellar granular neurons. Intra-peritoneal injection of ALLN to pregnant Lis1+/− dams rescued apoptotic neuronal cell death and neuronal migration defects in Lis1+/− offspring. Furthermore, in utero knockdown of calpain by shRNA rescued defective cortical layering in Lis1+/− mice. Thus, the inhibition of calpain is a potential therapeutic intervention for lissencephaly.
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DOI：
10.1083/jcb.100.2.384
发表时间：
1985-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hatten ME
通讯作者：
Hatten ME
影响因子：
5.3
作者：
Arthur, JSC;Elce, JS;Greer, PA
通讯作者：
Greer, PA
影响因子：
2.7
作者：
Saito, T;Nakatsuji, N
通讯作者：
Nakatsuji, N
影响因子：
7.7
作者：
Suzuki, K;Hata, S;Sorimachi, H
通讯作者：
Sorimachi, H
影响因子：
64.8
作者：
HATTORI, M;ADACHI, H;INOUE, K
通讯作者：
INOUE, K