2009年10月
Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly
NATURE MEDICINE
- 巻
- 15
- 号
- 10
- 開始ページ
- 1202
- 終了ページ
- U132
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/nm.2023
- 出版者・発行元
- NATURE PUBLISHING GROUP
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.
- リンク情報
- ID情報
-
- DOI : 10.1038/nm.2023
- ISSN : 1078-8956
- Web of Science ID : WOS:000270596400033