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

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

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 Β-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.

Original languageEnglish
Pages (from-to)1202-1207
Number of pages6
JournalNature Medicine
Volume15
Issue number10
DOIs
Publication statusPublished - 07-09-2009

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Lissencephaly
Calpain
Cytoplasmic Dyneins
Phenotype
Proteolysis
Enzyme inhibition
Mitochondria
Platelet Activating Factor
Cell death
Fibroblasts
Nervous System Diseases
Intraperitoneal Injections
Small Interfering RNA
Dams
Neurons
Protein Isoforms
Cell Death
Genes
Cells
Defects

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yamada, M., Yoshida, Y., Mori, D., Takitoh, T., Kengaku, M., Umeshima, H., ... Hirotsune, S. (2009). Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly. Nature Medicine, 15(10), 1202-1207. https://doi.org/10.1038/nm.2023
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. / Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly. In: Nature Medicine. 2009 ; Vol. 15, No. 10. pp. 1202-1207.
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Yamada, M, Yoshida, Y, Mori, D, Takitoh, T, Kengaku, M, Umeshima, H, Takao, K, Miyakawa, T, Sato, M, Sorimachi, H, Wynshaw-Boris, A & Hirotsune, S 2009, 'Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly', Nature Medicine, vol. 15, no. 10, pp. 1202-1207. https://doi.org/10.1038/nm.2023

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

In: Nature Medicine, Vol. 15, No. 10, 07.09.2009, p. 1202-1207.

Research output: Contribution to journalArticle

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AU - Kengaku, Mineko

AU - Umeshima, Hiroki

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AU - Miyakawa, Tsuyoshi

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AU - Wynshaw-Boris, Anthony

AU - Hirotsune, Shinji

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