Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly
Open Access
- 6 September 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 15 (10), 1202-1207
- https://doi.org/10.1038/nm.2023
Abstract
Lissencephaly is a developmental brain disorder caused by mutations in LIS1 and characterized by impaired neuronal migration. Inhibiting calpain prevents LIS1 degradation in heterozygous mice and rescues the defective neuronal migration in utero. 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.Keywords
This publication has 42 references indexed in Scilit:
- LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dyneinThe EMBO Journal, 2008
- Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disordersMolecular Brain, 2008
- Neuroepithelial Stem Cell Proliferation Requires LIS1 for Precise Spindle Orientation and Symmetric DivisionCell, 2008
- Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migrationHuman Molecular Genetics, 2005
- Calpain-mediated proteolysis of talin regulates adhesion dynamicsNature, 2004
- Vinculin is proteolyzed by calpain during platelet aggregation: 95 kDa cleavage fragment associates with the platelet cytoskeletonCell Motility, 2004
- Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migrationThe Journal of cell biology, 2004
- Calpain-mediated Cleavage of the Cyclin-dependent Kinase-5 Activator p39 to p29Published by Elsevier BV ,2002
- Disruption of the Murine Calpain Small Subunit Gene, Capn4: Calpain Is Essential for Embryonic Development but Not for Cell Growth and DivisionMolecular and Cellular Biology, 2000
- The Splay Angle: A New Measure for Assessing Neuromuscular Dysfunction in RatsPhysiology & Behavior, 1999