Xi Chen, Sudhanva Kashyap, Hannah McCue, James Johnson, Jeff Barclay, Bob Burgoyne and Alan Morgan.

Department of Cellular and Molecular Physiology, University of Liverpool, United Kingdom.

Adult onset neuronal lipofuscinosis (ANCL) is a human neurodegenerative disorder that results in progressive neuronal dysfunction and premature death. Recently, the mutations that cause ANCL have been mapped to the DNAJC5 gene, which encodes a synaptic vesicle-localised member of the DnaJ family of co-chaperones known as cysteine string protein (CSP). Drosophila and mouse CSP mutants are characterized by sensorimotor dysfunction, pre-synaptic neurodegeneration and premature mortality, indicating that CSP is an evolutionarily conserved neuroprotective protein. Identifying compounds that can rescue the neurodegeneration induced by loss of CSP function may therefore represent a potential therapeutic approach for ANCL and other neurodegenerative diseases. To this end, we have characterised the single DNAJC5 homologue in the worm C. elegans: dnj-14. Impairment of dnj-14 function using deletion mutations or RNAi resulted in a reduced lifespan compared to wild-type control worms. Mutant dnj-14 worms also exhibited age-dependent neurodegeneration, as indicated by reduced neuronal fluorescence using a pan-neuronal Prab-3::GFP marker. This was particularly notable in sensory neurons in the head. Consistent with this, dnj-14 mutants displayed a profound age-dependent chemosensory defect. A focused chemical screen revealed that resveratrol could ameliorate the short lifespan, chemosensory defect and neurodegenerative phenotypes of dnj-14 null mutant worms. The protective action of resveratrol was mimicked by the cAMP phosphodiesterase inhibitor, rolipram, consistent with recent data suggesting that resveratrol acts via PDE inhibition. However, activation of the Sirtuin, SIR-2.1, was not required, as sir-2.1;dnj-14 double mutants showed full lifespan rescue by resveratrol. A second hit compound from the screen not only rescued the dnj-14 mutant phenotypes, but also rescued distinct C. elegans neurodegeneration models based on expression of mutant human tau or polyglutamine expansions. Furthermore, transcriptomic analysis of drug-treated worms suggests that this compound’s neuroprotective mechanism of action involves the activation of specific transcription factors. We conclude that the dnj-14 model may be a useful new platform to screen for neuroprotective drugs with therapeutic potential not only for ANCL, but also for more common human neurodegenerative diseases.