Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.
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.
Yamada
Masami
M
Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Asahi-machi, Osaka, Japan.
Yoshida
Yuko
Y
Mori
Daisuke
D
Takitoh
Takako
T
Kengaku
Mineko
M
Umeshima
Hiroki
H
Takao
Keizo
K
Miyakawa
Tsuyoshi
T
Sato
Makoto
M
Sorimachi
Hiroyuki
H
Wynshaw-Boris
Anthony
A
Hirotsune
Shinji
S
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000235:genetics; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D054082:Lissencephaly; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010641:Phenotype; D011247:Pregnancy
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008869:Microtubule-Associated Proteins; C063261:acetylleucyl-leucyl-norleucinal; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D002154:Calpain; D004398:Dyneins; D007930:Leucine; C108192:aloxistatin