RRC ID 4181
Author Nyamsuren O, Faggionato D, Loch W, Schulze E, Baumeister R.
Title A mutation in CHN-1/CHIP suppresses muscle degeneration in Caenorhabditis elegans.
Journal Dev. Biol.
Abstract Duchenne muscular dystrophy (DMD) is one of the most severe X-linked, inherited diseases of childhood, characterized by progressive muscle wasting and weakness as the consequence of mutations in the dystrophin gene. The protein encoded by dystrophin is a huge cytosolic protein that links the intracellular F-actin filaments to the members of the dystrophin-glycoprotein-complex (DGC). Dystrophin deficiency results in the absence or reduction of complex components that are degraded through an unknown pathway. We show here that muscle degeneration in a Caenorhabditis elegans DMD model is efficiently reduced by downregulation of chn-1, encoding the homologue of the human E3/E4 ubiquitylation enzyme CHIP. A deletion mutant of chn-1 delays the cell death of body-wall muscle cells and improves the motility of animals carrying mutations in dystrophin and MyoD. Elimination of chn-1 function in the musculature, but not in the nervous system, is sufficient for this effect, and can be phenocopied by proteasome inhibitor treatment. This suggests a critical role of CHIP/CHN-1-mediated ubiquitylation in the control of muscle wasting and degeneration and identifies a potential new drug target for the treatment of this disease.
Volume 312(1)
Pages 193-202
Published 2007-12-1
DOI 10.1016/j.ydbio.2007.09.033
PII S0012-1606(07)01371-1
PMID 17961535
MeSH Actin Cytoskeleton / metabolism Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics* Caenorhabditis elegans Proteins / genetics* Cell Count Cell Movement / drug effects Cell Nucleus / drug effects Cell Nucleus / metabolism Genes, Helminth Leupeptins / pharmacology Muscle, Skeletal / cytology Muscle, Skeletal / drug effects Muscular Dystrophy, Animal / genetics* Muscular Dystrophy, Animal / pathology Mutation / genetics* Myosins / metabolism Phalloidine Ubiquitin-Protein Ligases / genetics*
IF 2.936
Times Cited 8
C.elegans tm1380 tm395