Intermittent fasting reduces alpha-synuclein pathology and functional decline in a mouse model of Parkinson's disease [asyn]

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the degeneration of the nigrostriatal dopaminergic neurons, and by intraneuronal accumulation of aggregated a-synuclein (aSyn). Environmental factors contribute significantly to neurodegeneration in patients, and non-pharmacological interventions are increasingly explored. Among these, caloric restriction and time-restricted feeding have demonstrated beneficial effects in animal models of neurodegenerative diseases. The ketone body ß-hydroxybutyrate (BHB) has been suggested to mediate some of these effects. In this study, we tested the therapeutic potential of intermittent fasting (IF, every other day feeding) in an aSyn-based mouse model of PD. IF was initiated four weeks after induction of aSyn pathology. Four weeks of IF mitigated the aSyn-induced degeneration of dopaminergic neurons and axon terminals. IF also reduced aSyn pathology as reported by staining for phosphorylated aSyn and Triton X-100 solubility. IF mitigated the aSyn-induced motor phenotype, the decrease in striatal dopamine and the decrease in synaptic markers. In transcriptomic analysis, we observed a robust modulation of genes involved in inflammation and microglia activation even with just brief IF treatment and without synuclein transduction. In primary mouse neurons, starvation and treatment with BHB were sufficient to induce autophagy and reduced aSyn pathology. Taken together, IF might constitute a plausible neuroprotective strategy for patients with Parkinson's diseases. BHB-induced autophagy and altered neuroinflammation are pathways that potentially contribute to the protective effect. Overall design: To investigate to effects of intermitted fasting on mesencephalic signalling in a rAAV-A53T-aSynuclein mouse model of parkinson's disease. We performed RNA-seq analysis to identify and characterize key pathways.