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

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Kashyap, SS, Johnson, JR ORCID: 0000-0002-8849-0993, McCue, Hannah, Chen, X, Edmonds, MJ, Ayala, M, Graham, ME, Jenn, RC, Barclay, Jeff, Burgoyne, Bob ORCID: 0000-0002-9219-0387 et al (show 1 more authors) (2014) 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. Human Molecular Genetics, 23 (22). pp. 5916-5927.

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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.

Item Type:	Article
Uncontrolled Keywords:	Phenotype, Mutation, Adult, Caenorhabditis elegans, Cysteine, Genes, Locomotion, Nerve degeneration, Neurodegenerative disorders, Neuronal ceroid-lipofuscinoses, Neurons, Afferent, Neuroprotective agents, Rolipram, Synaptic transmission, Helminths, Resveratrol, Sirtuins, Life span
Depositing User:	Symplectic Admin
Date Deposited:	10 Nov 2014 14:39
Last Modified:	16 Dec 2022 12:32
DOI:	10.1093/hmg/ddu316
Publisher's Statement :	This is a pre-copy edited, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Sudhanva S. Kashyap, James R. Johnson, Hannah V. McCue, Xi Chen, Matthew J. Edmonds, Mimieveshiofuo Ayala, Margaret E. Graham, Robert C. Jenn, Jeff W. Barclay, Robert D. Burgoyne, and Alan Morgan 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 Hum. Mol. Genet. (2014) 23 (22): 5916-5927 first published online June 19, 2014 doi:10.1093/hmg/ddu316 is available online at: http://hmg.oxfordjournals.org/content/23/22/5916.full.pdf+html
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2000941