title: Altered Function of the DnaJ Family Cochaperone DNJ-17 Modulates Locomotor Circuit Activity in a Caenorhabditis elegans Seizure Model.
abstract: The highly conserved cochaperone DnaJ/Hsp40 family proteins are known to interact with molecular chaperone Hsp70, and can regulate many cellular processes including protein folding, translocation, and degradation. In studies of Caenorhabditis elegans locomotion mutants, we identified a gain-of-function (gf) mutation in dnj-17 closely linked to the widely used e156 null allele of C. elegans GAD (glutamic acid decarboxylase) unc-25 dnj-17 encodes a DnaJ protein orthologous to human DNAJA5. In C. elegans DNJ-17 is a cytosolic protein and is broadly expressed in many tissues. dnj-17(gf) causes a single amino acid substitution in a conserved domain, and behaves as a hypermorphic mutation. The effect of this dnj-17(gf) is most prominent in mutants lacking GABA synaptic transmission. In a seizure model caused by a mutation in the ionotropic acetylcholine receptor acr-2(gf), dnj-17(gf) exacerbates the convulsion phenotype in conjunction with absence of GABA. Null mutants of dnj-17 show mild resistance to aldicarb, while dnj-17(gf) is hypersensitive. These results highlight the importance of DnaJ proteins in regulation of C. elegans locomotor circuit, and provide insights into the in vivo roles of DnaJ proteins in humans.
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California, 92093.
authors.forename: Seika
authors.initials: S
authors.lastname: Takayanagi-Kiya
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California, 92093 Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California, 92093 yijin@ucsd.edu.
authors.forename: Yishi
authors.identifier: 0000-0002-9371-9860
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000448:Aldicarb / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001522:Behavior, Animal; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D017124:Conserved Sequence; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008124:Locomotion; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics; D012640:Seizures / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D009435:Synaptic Transmission / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000172:deficiency
chemical_list: C098140:Acr-2 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002800:Cholinesterase Inhibitors; C000618996:DNAJC21 protein, human; D050956:HSP40 Heat-Shock Proteins; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; D000448:Aldicarb; D005968:Glutamate Decarboxylase
keywords: GABA; acetylcholine receptor; excitation; glutamic acid decarboxylase; inhibition balance