As human populations age, neurodegenerative diseases are becoming an increasing burden. The underlying mechanisms that cause age-dependent loss of neurons in these diseases remain unclear. As a result, therapies for these debilitating and eventually fatal disorders are lacking. One way to address this problem is by the use of model organisms like C. elegans to understand the mechanisms of neurodegeneration and for screening novel drug targets. Here we describe a new C. elegans model for age-dependent neurodegeneration caused by mutation of the
dnj-14 gene. DNJ-14 is the worm homologue of cysteine string protein (CSP), a neuronal chaperone protein which prevents the misfolding of presynaptic proteins. Mutations in CSP cause Adult-onset Neuronal Ceroid Lipofuscinosis (ANCL), a human neurodegenerative disease. CSP knockout mice have early mortality and exhibit age-related neurotransmission defects, sensorimotor dysfunction and presynaptic neurodegeneration. We show here that mutations in C. elegans'
dnj-14 also result in a significant reduction in lifespan, small reduction in locomotion and resistance to aldicarb (a behavioural read-out of cholinergic neurotransmission). The worms also show age-dependent defects in chemosensation which correlated to the loss of sensory neurons at a later age. Treatment with resveratrol, a polyphenol that has been previously shown to be neuroprotective in several neurodegenerative disease models, rescues the lifespan and the chemosensation defects in the
dnj-14 mutant worms. Resveratrol also rescues the lifespan of
dnj-14 mutants lacking
sir-2.1. Similarly, a PDE-4 inhibitor, rolipram also rescues the lifespan of
dnj-14 worms. This suggests that resveratrol acts in a PDE-4 inhibition dependent and
sir-2.1 independent manner. Hence we show that this new worm model could be useful in screening novel neuroprotective compounds.