期刊
NATURE MEDICINE
卷 15, 期 10, 页码 1202-U132出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2023
关键词
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资金
- Ministry of Education, Science, Sports and Culture of Japan
- Sagawa Foundation for Promotion of Cancer Research
- The Cell Science Research Foundation
- The Japan Spina Bifida & Hydrocephalus Research Foundation
- Takeda Science Foundation
- The Hoh-ansha Foundation
- Knowledge Cluster Initiative (Stage-2) Research Foundation
- US National Institutes of Health [NS41030, HD47380]
- MEXT
- Neuroinformatics Japan Center
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD047380] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS041030] Funding Source: NIH RePORTER
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.
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