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
Adult onset neuronal lipofuscinosis (ANCL) is a human neurodegenerative disorder characterized by progressive neuronaldysfunction 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-independentneuroprotective action of resveratrol revealed here suggests potential therapeutic applications for ANCL and possibly other human neurodegenerative diseases.
El resveratrol puede proporcionar un tratamiento eficaz para una enfermedad neurodegenerativa mortal conocida como lopofuscinosis ceroide neuronal del adulto (ANCL). Este estudio permite probar rápidamente los compuestos que podrían ser utilizados para el tratamiento. La ANCL afecta a aproximadamente uno de cada 100 mil personas en Europa y América del Norte, generalmente a adultos de 30 años. Hasta ahora, los investigadores no han podido encontrar ningún tratamiento para la enfermedad.
Resveratrol may provide an effective treatment for a fatal neurodegenerative disease known as adult onset neuronal ceroid lipofuscinosis (ANCL). This study allows to quickly test compounds that could be used for treatment. ANCL affects about one in 100,000 people in Europe and North America, usually adults around 30 years old. Until now, researchers have been unable to find any treatment for the disease.