Reference - Detail
|Author||Kashyap SS, Johnson JR, McCue HV, Chen X, Edmonds MJ, Ayala M, Graham ME, Jenn RC, Barclay JW, Burgoyne RD, Morgan A.|
|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.|
|Journal||Hum. Mol. Genet.|
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.
|MeSH||Adult Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Disease Models, Animal* Drug Evaluation, Preclinical HSP40 Heat-Shock Proteins / genetics HSP40 Heat-Shock Proteins / metabolism* Humans Life Expectancy Membrane Proteins / genetics Membrane Proteins / metabolism* Neuronal Ceroid-Lipofuscinoses / drug therapy Neuronal Ceroid-Lipofuscinoses / genetics Neuronal Ceroid-Lipofuscinoses / metabolism* Sirtuins / genetics Sirtuins / metabolism* Stilbenes / pharmacology*|
|WOS Category||GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY|