Collins, James J. et al. (2009) International Worm Meeting "The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans life span."

Kornfeld, Kerry, Collins, James J., Pickett, Christopher L., Schneider, Daniel L., Evason, Kimberley

[International Worm Meeting, 2009]

Ethosuximide is a medication used to treat seizure disorders in humans. We previously demonstrated that ethosuximide could delay age-related changes and extend the life span of C. elegans. The mechanism of action of ethosuximide in life span extension is unknown, and elucidating how ethosuximide functions is important for defining endogenous processes that influence life span and for exploring the potential of ethosuximide as a therapeutic for age-related diseases. To identify factors that mediate the activity of ethosuximide, we conducted a genetic screen and identified mutations in two genes, che-3 and osm-3, that confer resistance to ethosuximide-mediated toxicity. Mutations in che-3 and osm-3 cause defects in an overlapping set of chemosensory neurons, resulting in defective chemosensation and life span extension. These findings suggest that ethosuximide extends life span by inhibiting the function of specific chemosensory neurons. This model is supported by the observation that ethosuximide treated animals displayed numerous phenotypic similarities with mutants that have chemosensory defects. Furthermore, long-lived osm-3 animals were resistant to the life span extension caused by ethosuximide, suggesting the drug extends life span by inhibiting chemosensation. These studies demonstrate a novel mechanism of action for a life span extending drug and indicate that sensory perception has a critical role in controlling life span. Sensory perception also influences the life span of Drosophila, suggesting that sensory perception has an evolutionarily conserved role in life span control. These studies highlight the potential of ethosuximide and related drugs that modulate sensory perception to extend life span in diverse animals.

James J Collins et al. (2005) International Worm Meeting "A genetic screen to characterize anticonvulsant mediated lifespan extension in C. elegans"

Kerry Kornfeld, James J Collins, Kimberley J Evason

[International Worm Meeting, 2005]

The succinimide based anticonvulsant compounds ethosuximde and trimethadione are capable of extending C. elegans lifespan and delaying aging related functional declines. These compounds were able to extend the lifespan of daf-16 mutants, suggesting a daf-16 independent mechanism of lifespan extension. To further analyze how these drugs extend lifespan, we are identifying genes that mediate the effects of these drugs. Ethosuximide and trimethadione cause optimal lifespan extension at external concentrations of about 2 mg/ml, and cause a fully penetrant lethal phenotype at about 12 mg/ml. We screened for chemically induced mutations that enable animals to survive exposure to toxic doses of ethosuximide and trimethadione. We screened about 270,000 haploid genomes and identified 52 resistant mutants. Several of these mutants have now been backcrossed and analyzed for lifespan in the presence and absence of the drugs. Some of these mutants are partially or completely resistant to the lifespan extension caused by the drugs, indicating that the effected gene plays a role in regulating lifespan.

Butler JA et al. (1994) Worm Breeder's Gazette "Looking For Extracellular Matrix Proteinases in C. elegans"

Kramer JM, Butler JA

[Worm Breeder's Gazette, 1994]

LOOKING FOR EXTRACELLULAR MATRIX PROTEINASES IN C. ELEGANS. James A. Butler and James M. Kramer, Northwestern University Medical School. Department of CMS Biology, Chicago IL 60611

Almeida CA et al. (1994) Worm Breeder's Gazette "Function of a Domain of the Myosin Heavy Chain Implicated in Familial Hypertrophic Cardiomyopathy"

Collins JJ, Almeida CA, Swift KE

[Worm Breeder's Gazette, 1994]

Function of a Domain of the Myosin Heavy Chain Implicated in Familial Hypertrophic Cardiomyopathy Craig A. Almeida, Kerry E. Swift and John J. Collins Department of Biochemistry and Molecular, University of New Hampshire, Durham, NH 03820

Wissmann AK et al. (1994) Worm Breeder's Gazette "Characterization of the let-502 Gene"

Mains PE, Wissmann AK, McGhee JD

[Worm Breeder's Gazette, 1994]

Characterization of the let-502 gene Andreas Wissmann, James D. McGhee and Paul E. Mains, Dept. of Medical Biochemistry, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Parham C et al. (1994) Worm Breeder's Gazette "Tc4 and Tc5: What Makes Them Move and Why It Matters"

Beinhorn J, Collins JJ, Butze K, Parham C

[Worm Breeder's Gazette, 1994]

Tc4 and Tc5: what makes them move and why it matters Christi Parham, Kristie Butze, Joanna Beinhorn and John Collins. Dept. of Biochemistry and Molecular Biology, University of New Hampshire. Durham, NH 03824

McGhee JD (1987) Biochemistry "Purification and characterization of a carboxylesterase from the intestine of the nematode Caenorhabditis elegans."

McGhee JD

[Biochemistry, 1987]

The major intestinal esterase from the nematode Caenorhabditis elegans has been purified to essential homogeneity. Starting from whole worms, the overall purification is 9000-fold with a 10% recovery of activity. The esterase is a single polypeptide chain of Mr 60,000 and is stoichiometrically inhibited by organophosphates. Substrate preferences and inhibition patterns classify the enzyme as a carboxylesterase (EC 3.1.1.1), but the physiological function is unknown. The sequence of 13 amino acid residues at the esterase N- terminus has been determined. This partial sequence shows a surprisingly high degree of similarity to the N-terminal sequence of two carboxylesterases recently isolated from Drosophila mojavensis [Pen, J., van Beeumen, J., & Beintema, J. J. (1986) Biochem. J. 238, 691-699].

Murakami S et al. (1999) Curr Biol "Life extension and stress resistance in Caenorhabditis elegans modulated by the tkr-1 gene."

Johnson TE, Murakami S

[Curr Biol, 1999]

In this Brief Communication, which appeared in the 14 September 1998 issue of Current Biology, the UV dose was reported erroneously. The dose reported was 20 J/m2 but the actual dose used was 0.4 J/cm2. Also, the gene formally referred to as tkr-1 has since been renamed old-1 (overexpression longevity determination).

Ramos CG et al. (2014) J Bacteriol "Retraction for Ramos et al., MtvR is a global small noncoding regulatory RNA in Burkholderia cenocepacia."

Feliciano JR, da Costa PJ, Ramos CG, Grilo AM, Leitao JH

[J Bacteriol, 2014]

Volume 195, no. 16, p. 35143523, 2013. A number of problems related to images published in this paper have been brought to our attention. Figure 1D contains duplicated images in lanes S and LE, and Fig. 4D and 6B contain images previously published in articles in this journal and in Microbiology and Microbial Pathogenesis, i.e., the following: C. G. Ramos, S. A. Sousa, A. M. Grilo, J. R. Feliciano, and J. H. Leitao, J. Bacteriol. 193:15151526, 2011. doi:10.1128/JB.01374-11. S. A. Sousa, C. G. Ramos, L. M. Moreira, and J. H. Leitao, Microbiology 156:896908, 2010. doi:10.1099/mic.0.035139-0. C. G. Ramos, S. A. Sousa, A. M. Grilo, L. Eberl, and J. H. Leitao, Microb. Pathog. 48:168177, 2010. doi: 10.1016/j.micpath.2010.02.006. Therefore, we retract the paper. We deeply regret this situation and apologize for any inconvenience to the editors and readers of Journal of Bacteriology, Microbial Pathogenesis, and Microbiology.

Nillegoda NB et al. (2015) Nature "Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation."

Berynskyy M, Morimoto RI, Bukau B, Stengel F, Kirstein J, Szlachcic A, Arnsburg K, Stank A, Scior A, Nillegoda NB, Gao X, Guilbride DL, Aebersold R, Wade RC, Mayer MP

[Nature, 2015]

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.