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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.

human molecular genetics

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