Effects of diet on synaptic vesicle release in dynactin complex mutants: a mechanism for improved vitality during motor disease

Synaptic dysfunction is considered the primary substrate for the functional declines observed within the nervous system during age-related neurodegenerative disease. Dietary restriction (DR), which extends lifespan in numerous species, has been shown to have beneficial effects on many neurodegenerative disease models. Existing data sets suggest that the effects of DR during disease include the amelioration of synaptic dysfunction but evidence of the beneficial effects of diet on the synapse is lacking. Dynactin mutant flies have significant increases in mortality rates and exhibit progressive loss of motor function. Using a novel fly motor disease model, we demonstrate that mutant flies raised on a low calorie diet have enhanced motor function and improved survival compared to flies on a high calorie diet. Neurodegeneration in this model is characterized by an early impairment of neurotransmission that precedes the deterioration of neuromuscular junction (NMJ) morphology. In mutant flies, low calorie diet increases neurotransmission, but has little effect on morphology, supporting the hypothesis that enhanced neurotransmission contributes to the effects of diet on motor function. Importantly, the effects of diet on the synapse are not because of the reduction of mutant pathologies, but by the increased release of synaptic vesicles during activity. The generality of this effect is demonstrated by the observation that diet can also increase synaptic vesicle release at wild-type NMJs. These studies reveal a novel presynaptic mechanism of diet that may contribute to the improved vigor observed in mutant flies raised on low calorie diet.