Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Int J Biochem Cell Biol. 2010 Sep;42(9):1401-7. doi: 10.1016/j.biocel.2010.05.017. Epub 2010 Jun 9.

A novel strategy for therapeutic intervention for the genetic disease: preventing proteolytic cleavage using small chemical compound.

Author information

  • 1Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Asahimachi 1-4-3 Abeno, Osaka 545-8585, Japan.

Abstract

Haploinsufficiency is a state of genetic disease, which is caused by hemizygous mutations of functional alleles. Lissencephaly is a typical example of haploinsufficiency disorders characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricules associated with mental retardation and seizures due to defective neuronal migration. LIS1 was the first gene cloned in an organism, which was deleted or mutated in patients with lissencephaly in a heterozygous fashion. Series of studies uncovered that LIS1 is an essential regulator of cytoplasmic dynein. In particular, we reported that LIS1 is essential for dynein transport to the plus-end of microtubules by kinesin, which is essential for maintaining proper distribution of cytoplasmic dynein within the cell. Fortuitously, we found that a substantial fraction of LIS1 is degraded by the cystein protease, calpain after reaching the plus-end of microtubules. We further demonstrated that inhibition of calpain-mediated LIS1 degradation increased LIS1 level at the cortex of the cell, resulting in therapeutic benefit using genetic mouse models with reduced levels of LIS1. Our work might provide a potential therapeutic approach for the treatment of a fraction of haploinsufficiency disorders through augmenting reduced proteins by the targeting inhibition of degradation machinery.

Copyright (c) 2010 Elsevier Ltd. All rights reserved.

PMID:
20541031
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Elsevier Science
    Loading ...
    Write to the Help Desk