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.
Highlights
Age-related neurodegenerative diseases have a devastating impact on affected individuals and pose a significant economic challenge for society
The C. elegans genome encodes a single homologue of the DNAJC5 gene that is mutated in ANCL: dnj-14
As mutations in DNAJC5 homologues are associated with reduced lifespan in humans (7 – 10), mice [16] and flies [11], we performed lifespan analysis on dnj-14(ok237) and wild-type N2 worms
Summary
Age-related neurodegenerative diseases have a devastating impact on affected individuals and pose a significant economic challenge for society. There is a pressing need to identify molecular and cellular neuroprotective mechanisms that decline with ageing so that drugs can be developed to modulate the neurodegenerative process and extend health-span. Human genetic studies have successfully identified single gene mutations in various neurodegenerative disorders. Frontotemporal dementia, Parkinson’s and Huntington’s diseases are associated with alterations in genes encoding tau, a-synuclein and huntingtin, respectively [1]. Studies on animal models using genetic or pharmacological approaches have shown that altering the activity of molecular chaperones, proteasomes and autophagy can be neuroprotective (2 – 5). Drugs targeting these processes represent promising candidate therapies
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