Doc IdWBPaper00040962
titleThe Atypical Calpains : Evolutionary Analyses and Roles in Caenorhabditis elegans Cellular Degeneration .
authorJoyce PI ; Satija R ; Chen M ; Kuwabara PE
journalPLoS Genet
year2012-03
citationV : 8 P : e1002602
typeJournal_article
abstractThe calpains are physiologically important Ca ( 2 + ) -activated regulatory proteases , which are divided into typical or atypical sub-families based on constituent domains . Both sub-families are present in mammals , but our understanding of calpain function is based primarily on typical sub-family members . Here , we take advantage of the model organism Caenorhabditis elegans , which expresses only atypical calpains , to extend our knowledge of the phylogenetic evolution and function of calpains . We provide evidence that a typical human calpain protein with a penta EF hand , detected using custom profile hidden Markov models , is conserved in ancient metazoans and a divergent clade . These analyses also provide evidence for the lineage-specific loss of typical calpain genes in C . elegans and Ciona , and they reveal that many calpain-like genes lack an intact catalytic triad . Given the association between the dysregulation of typical calpains and human degenerative pathologies , we explored the phenotypes , expression profiles , and consequences of inappropriate reduction or activation of C . elegans atypical calpains . These studies show that the atypical calpain gene , clp-1 , contributes to muscle degeneration and reveal that clp-1 activity is sensitive to genetic manipulation of [ Ca ( 2 + ) ] ( i ) . We show that CLP-1 localizes to sarcomeric sub-structures , but is excluded from dense bodies ( Z-disks ) . We find that the muscle degeneration observed in a C . elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca ( 2 + ) dysfunction underlies the C . elegans MyoD model of myopathy . Taken together , our analyses highlight the roles of calcium dysregulation and CLP-1 in muscle myopathies and suggest that the atypical calpains could retain conserved roles in myofilament turnover .
pdfWBPaper00040962
Matching sentences
field: abstract
Sen. 9: We find that the muscle degeneration observed in a C . elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca ( 2 + ) dysfunction underlies the C . elegans MyoD model of myopathy .
field: introduction
Sen. 10: We find that the muscle degeneration observed in a C . elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca2 + dysfunction underlies the C . elegans MyoD model of myopathy .
Sen. 45: Previous work in C . elegans has highlighted the importance of the tra-3 / clp-5 calpain gene in sex determination [ 33 , 34 ] ; other studies have shown that the C . elegans clp-1 and tra-3 / clp-5 genes are involved in neurodegeneration and necrosis of a subset of vulval cells and in the intestine [ 3537 ] .
Sen. 48: Given the association between calpain activity and degenerative pathologies , we have investigated factors that influence the activity of clp-1 in a C . elegans model of muscular dystrophy and reveal the importance of both sustained calpain expression and intracellular Ca2 + levels ( [ Ca2 + ] i ) .
field: results
Sen. 25: We find that CLP-1 contributes to the muscle degeneration observed in a model of Duchenne muscular dystrophy .
Sen. 132: Reduction of CLP-1 activity suppresses muscle degeneration in a C . elegans model of muscular dystrophy In mammals , the absence of the large structural muscle protein dystrophin underlies the muscle degenerative disorder Duchenne muscular dystrophy ( DMD ) [ 63 ] .
field: discussion
Sen. 44: Nonetheless , removal of clp-1 substantially suppressed the muscle degeneration associated with C . elegans dys-1 ; hlh-1 ( cc561ts ) DMD , which is based on a mouse model of myopathy involving the combined mutation of MyoD and dystrophin ( Table 2 ) [ 60 , 76 ] .

Doc IdWBPaper00040976
titleGenetics , Life Span , Health Span , and the Aging Process in Caenorhabditis elegans .
authorTissenbaum HA
journalJ Gerontol A Biol Sci Med Sci
year2012-04-12
citation
typeJournal_article
abstractAs a tool for measuring the aging process , life span has been invaluable in dissecting the genes that modulate longevity . Studies over the past few decades have identified several hundred genes that can modify life span in model organisms such as yeast , worms , and flies . Yet , despite this vast amount of research , we still do not fully understand how the genes that affect life span influence how an organism ages . How does modulation of the genes that affect life span contribute to the aging process ? Does life-span extension result in extension of healthy aging ? Here , we will focus primarily on the insulin / IGF-1 signaling pathway in Caenorhabditis elegans because members of this pathway have been shown to be associated with extended life span across phylogeny , from worms to humans . I discuss how this connects to the aging process , age-associated disease , and the potential to increase healthy aging in addition to lengthening life span .
pdfWBPaper00040976
Matching sentences
field: introduction
Sen. 206: In the C . elegans Parkinson ' s disease model , the dat-1 promoter was fused to green fluorescence protein and specifically expressed in eight dopaminergic neurons .