title: Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol.
abstract: Adult onset neuronal lipofuscinosis (ANCL) is a human neurodegenerative disorder characterized by progressive neuronal dysfunction and premature death. Recently, the mutations that cause ANCL were mapped to the DNAJC5 gene, which encodes cysteine string protein alpha. We show here that mutating dnj-14, the Caenorhabditis elegans orthologue of DNAJC5, results in shortened lifespan and a small impairment of locomotion and neurotransmission. Mutant dnj-14 worms also exhibited age-dependent neurodegeneration of sensory neurons, which was preceded by severe progressive chemosensory defects. A focussed chemical screen revealed that resveratrol could ameliorate dnj-14 mutant phenotypes, an effect mimicked by the cAMP phosphodiesterase inhibitor, rolipram. In contrast to other worm neurodegeneration models, activation of the Sirtuin, SIR-2.1, was not required, as sir-2.1; dnj-14 double mutants showed full lifespan rescue by resveratrol. The Sirtuin-independent neuroprotective action of resveratrol revealed here suggests potential therapeutic applications for ANCL and possibly other human neurodegenerative diseases.
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Sudhanva S
authors.initials: SS
authors.lastname: Kashyap
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Johnson
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Hannah V
authors.initials: HV
authors.lastname: McCue
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Edmonds
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Mimieveshiofuo
authors.initials: M
authors.lastname: Ayala
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Graham
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Jenn
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Barclay
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burgoyne
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool L69 3BX, UK amorgan@liverpool.ac.uk.
authors.forename: Alan
authors.initials: A
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008017:Life Expectancy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D013267:Stilbenes; C088460:cysteine string protein; C507014:SIR-2.1 protein, C elegans; D037761:Sirtuins; D000077185:Resveratrol