• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

抑制钙蛋白酶可增加LIS1的表达，并在无脑回畸形小鼠模型中部分挽救体内表型。

Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.

作者信息

Yamada Masami, Yoshida Yuko, Mori Daisuke, Takitoh Takako, Kengaku Mineko, Umeshima Hiroki, Takao Keizo, Miyakawa Tsuyoshi, Sato Makoto, Sorimachi Hiroyuki, Wynshaw-Boris Anthony, Hirotsune Shinji

机构信息

Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Asahi-machi, Osaka, Japan.

出版信息

Nat Med. 2009 Oct;15(10):1202-7. doi: 10.1038/nm.2023. Epub 2009 Sep 6.

DOI:10.1038/nm.2023
PMID:19734909
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2759411/
Abstract

Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. LIS1 (official symbol PAFAH1B1, for platelet-activating factor acetylhydrolase, isoform 1b, subunit 1) was identified as the gene mutated in individuals with lissencephaly, and it was found to regulate cytoplasmic dynein function and localization. Here we show that inhibition or knockdown of calpains protects LIS1 from proteolysis, resulting in the augmentation of LIS1 amounts in Lis1(+/-) mouse embryonic fibroblast cells and rescue of the aberrant distribution of cytoplasmic dynein, mitochondria and beta-COP-positive vesicles. We also show that calpain inhibitors improve neuronal migration of Lis1(+/-) cerebellar granular neurons. Intraperitoneal injection of the calpain inhibitor ALLN to pregnant Lis1(+/-) dams rescued apoptotic neuronal cell death and neuronal migration defects in Lis1(+/-) offspring. Furthermore, in utero knockdown of calpain by short hairpin RNA rescued defective cortical layering in Lis1(+/-) mice. Thus, calpain inhibition is a potential therapeutic intervention for lissencephaly.

摘要

无脑回畸形是一种由神经元迁移缺陷引起的严重神经系统疾病。LIS1（官方符号为PAFAH1B1，即血小板活化因子乙酰水解酶，同工型1b，亚基1）被鉴定为无脑回畸形患者中发生突变的基因，并且发现它可调节胞质动力蛋白的功能和定位。在此我们表明，抑制或敲低钙蛋白酶可保护LIS1不被蛋白水解，从而导致Lis1(+/-)小鼠胚胎成纤维细胞中LIS1量的增加，并挽救胞质动力蛋白、线粒体和β-COP阳性囊泡的异常分布。我们还表明，钙蛋白酶抑制剂可改善Lis1(+/-)小脑颗粒神经元的神经元迁移。向怀孕的Lis1(+/-)母鼠腹腔注射钙蛋白酶抑制剂ALLN可挽救Lis1(+/-)后代中凋亡性神经元细胞死亡和神经元迁移缺陷。此外，通过短发夹RNA在子宫内敲低钙蛋白酶可挽救Lis1(+/-)小鼠中缺陷的皮质分层。因此，抑制钙蛋白酶是无脑回畸形的一种潜在治疗干预措施。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/0b4b9c6ff330/nihms136988f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/67e9bfbc1808/nihms136988f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/79996524c244/nihms136988f2a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/9f5a7f2ae4ba/nihms136988f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/aca14ae98d70/nihms136988f4a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/0b4b9c6ff330/nihms136988f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/67e9bfbc1808/nihms136988f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/79996524c244/nihms136988f2a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/9f5a7f2ae4ba/nihms136988f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/aca14ae98d70/nihms136988f4a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/855e/2759411/0b4b9c6ff330/nihms136988f5.jpg

相似文献

1
Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.抑制钙蛋白酶可增加LIS1的表达，并在无脑回畸形小鼠模型中部分挽救体内表型。
Nat Med. 2009 Oct;15(10):1202-7. doi: 10.1038/nm.2023. Epub 2009 Sep 6.
2
ALLN rescues an in vitro excitatory synaptic transmission deficit in Lis1 mutant mice.ALLN 挽救了 Lis1 突变小鼠体外兴奋性突触传递缺陷。
J Neurophysiol. 2013 Jan;109(2):429-36. doi: 10.1152/jn.00431.2012. Epub 2012 Oct 24.
3
[Molecular mechanism of lissencephaly--how LIS1 and NDEL1 regulate cytoplasmic dynein?].无脑回畸形的分子机制——LIS1和NDEL1如何调节胞质动力蛋白？
Brain Nerve. 2008 Apr;60(4):375-81.
4
Genetic enhancement of the Lis1+/- phenotype by a heterozygous mutation in the adenomatous polyposis coli gene.腺瘤性息肉病 coli 基因杂合突变对 Lis1+/- 表型的遗传增强作用。
Dev Neurosci. 2008;30(1-3):157-70. doi: 10.1159/000109860.
5
Distinct dose-dependent cortical neuronal migration and neurite extension defects in Lis1 and Ndel1 mutant mice.Lis1 和 Ndel1 突变小鼠皮质神经元迁移和突起延伸缺陷具有明显的剂量依赖性。
J Neurosci. 2009 Dec 9;29(49):15520-30. doi: 10.1523/JNEUROSCI.4630-09.2009.
6
A novel strategy for therapeutic intervention for the genetic disease: preventing proteolytic cleavage using small chemical compound.一种针对遗传疾病的治疗干预新策略：使用小分子化合物防止蛋白水解切割。
Int J Biochem Cell Biol. 2010 Sep;42(9):1401-7. doi: 10.1016/j.biocel.2010.05.017. Epub 2010 Jun 9.
7
LIS1 controls mitosis and mitotic spindle organization via the LIS1-NDEL1-dynein complex.LIS1 通过 LIS1-NDEL1-动力蛋白复合物控制有丝分裂和有丝分裂纺锤体的组织。
Hum Mol Genet. 2014 Jan 15;23(2):449-66. doi: 10.1093/hmg/ddt436. Epub 2013 Sep 12.
8
LIS1 functions in normal development and disease.LIS1 在正常发育和疾病中发挥作用。
Curr Opin Neurobiol. 2013 Dec;23(6):951-6. doi: 10.1016/j.conb.2013.08.001. Epub 2013 Aug 23.
9
Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development.无脑回畸形与LIS1：对神经元迁移和发育分子机制的见解
Clin Genet. 2007 Oct;72(4):296-304. doi: 10.1111/j.1399-0004.2007.00888.x.
10
Novel embryonic neuronal migration and proliferation defects in Dcx mutant mice are exacerbated by Lis1 reduction.Dcx 突变小鼠中新型胚胎神经元迁移和增殖缺陷因 Lis1 减少而加重。
J Neurosci. 2010 Feb 24;30(8):3002-12. doi: 10.1523/JNEUROSCI.4851-09.2010.

引用本文的文献

1
Presynaptic perspective: Axonal transport defects in neurodevelopmental disorders.突触前观点：神经发育障碍中的轴突运输缺陷。
J Cell Biol. 2024 Jun 3;223(6). doi: 10.1083/jcb.202401145. Epub 2024 Apr 3.
2
Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis.前脑早期发育中的线粒体：从神经胚形成到皮质中期发育
Front Cell Dev Biol. 2021 Nov 23;9:780207. doi: 10.3389/fcell.2021.780207. eCollection 2021.
3
Toward a Better Understanding of Neuronal Migration Deficits in Autism Spectrum Disorders.更好地理解自闭症谱系障碍中的神经元迁移缺陷

本文引用的文献

1
Increased LIS1 expression affects human and mouse brain development.LIS1表达增加会影响人类和小鼠的大脑发育。
Nat Genet. 2009 Feb;41(2):168-77. doi: 10.1038/ng.302. Epub 2009 Jan 11.
2
Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.α-CaMKII 缺乏导致不成熟的齿状回，一种精神疾病的新候选内表型。
Mol Brain. 2008 Sep 10;1:6. doi: 10.1186/1756-6606-1-6.
3
LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dynein.LIS1和NDEL1共同协调胞质动力蛋白向正端的运输。
Front Cell Dev Biol. 2019 Sep 20;7:205. doi: 10.3389/fcell.2019.00205. eCollection 2019.
4
Disorders of neurogenesis and cortical development.神经发生与皮质发育障碍。
Dialogues Clin Neurosci. 2018 Dec;20(4):255-266. doi: 10.31887/DCNS.2018.20.4/ccardoso.
5
Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3.与17号染色体p13.3微缺失和微重复相关的神经发育性遗传疾病
Front Genet. 2018 Mar 23;9:80. doi: 10.3389/fgene.2018.00080. eCollection 2018.
6
Administration of Drugs Targeting Microglia Improves the Neurodevelopmental Outcome Following Cytomegalovirus Infection of the Rat Fetal Brain.给予靶向小胶质细胞的药物可改善大鼠胎儿脑巨细胞病毒感染后的神经发育结局。
Front Cell Neurosci. 2018 Mar 6;12:55. doi: 10.3389/fncel.2018.00055. eCollection 2018.
7
Hepatic loss of () induces fatty liver and accelerates liver tumorigenesis in mice.（）缺失导致小鼠脂肪肝，并加速肝脏肿瘤发生。
J Biol Chem. 2018 Apr 6;293(14):5160-5171. doi: 10.1074/jbc.RA117.001474. Epub 2018 Feb 23.
8
An anti-CAPN5 intracellular antibody acts as an inhibitor of CAPN5-mediated neuronal degeneration.一种抗钙蛋白酶5细胞内抗体可作为钙蛋白酶5介导的神经元变性的抑制剂。
Oncotarget. 2017 Nov 1;8(59):100312-100325. doi: 10.18632/oncotarget.22221. eCollection 2017 Nov 21.
9
Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport.α-突触核蛋白有助于形成具有独特功能的短非常规微管，这种微管在轴突运输中起作用。
Sci Rep. 2017 Nov 27;7(1):16386. doi: 10.1038/s41598-017-15575-3.
10
Potential Role of Microtubule Stabilizing Agents in Neurodevelopmental Disorders.微管稳定剂在神经发育障碍中的潜在作用。
Int J Mol Sci. 2017 Jul 26;18(8):1627. doi: 10.3390/ijms18081627.
EMBO J. 2008 Oct 8;27(19):2471-83. doi: 10.1038/emboj.2008.182. Epub 2008 Sep 11.
4
Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division.神经上皮干细胞增殖需要LIS1来实现精确的纺锤体定向和对称分裂。
Cell. 2008 Feb 8;132(3):474-86. doi: 10.1016/j.cell.2008.01.026.
5
Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development.无脑回畸形与LIS1：对神经元迁移和发育分子机制的见解
Clin Genet. 2007 Oct;72(4):296-304. doi: 10.1111/j.1399-0004.2007.00888.x.
6
Tyrosine phosphorylation of the integrin beta 3 subunit regulates beta 3 cleavage by calpain.整合素β3亚基的酪氨酸磷酸化通过钙蛋白酶调节β3裂解。
J Biol Chem. 2006 Oct 6;281(40):29426-30. doi: 10.1074/jbc.C600039200. Epub 2006 Aug 25.
7
Pathogenesis of migration disorders.迁移障碍的发病机制。
Curr Opin Neurol. 2006 Apr;19(2):135-40. doi: 10.1097/01.wco.0000218228.73678.e1.
8
Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration.一种与LIS1相互作用的蛋白质——磷酸化的NDEL1对katanin p60的招募，对有丝分裂细胞分裂和神经元迁移至关重要。
Hum Mol Genet. 2005 Nov 1;14(21):3113-28. doi: 10.1093/hmg/ddi339. Epub 2005 Oct 3.
9
Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality.Ndel1的完全缺失会导致神经元迁移缺陷和早期胚胎致死。
Mol Cell Biol. 2005 Sep;25(17):7812-27. doi: 10.1128/MCB.25.17.7812-7827.2005.
10
Gait dynamics in mouse models of Parkinson's disease and Huntington's disease.帕金森病和亨廷顿舞蹈病小鼠模型中的步态动力学
J Neuroeng Rehabil. 2005 Jul 25;2:20. doi: 10.1186/1743-0003-2-20.