Isradipine Rescues Alpha-synuclein Toxicity in a ZebrafishModel of Parkinson’s Disease by Upregulating Autophagy (1II-2.004)

OBJECTIVE: To investigate the effect of isradipine, an L-type calcium channel blocker of the dihydropyridine class, on a genetic model of Parkinson’s disease pathology in zebrafish.BACKGROUND: Epidemiological data support the potential disease-modifying effect of exposure to dihydropyridine calcium channel blockers in Parkinson’s disease. Prior studies suggest this effect may be mediated through modulation of calcium toxicity in "pacemaker" dopaminergic neurons, despite the presence of Lewy pathology in other neuron types.Meanwhile, several L-type calcium-channel blockers have also been shown to induce autophagy, the lysosome-dependent process by which cells dispose of damaged organelles and protein aggregates. This process, implicated in a range of neurodegenerative disease, can dispose of toxic oligomers of alpha-synuclein.METHODS: Zebrafish overexpressing human alpha-synuclein were treated with isradipine and the effects on overall survival, induction of autophagy, and synuclein accumulation were measured. These results were also compared to those obtained in zebrafish in which autophagy was inhibited by morpholino knockdown of the autophagy-related protein LC3.RESULTS: Isradipine treatment upregulated autophagy as assessed by GFP-LC3 and significantly improved the survival of alpha-synuclein overexpressing zebrafish. The rescue was abrogated by knockdown of LC3.CONCLUSIONS: Isradipine treatment rescues neuronal toxicity in an alpha-synuclein overexpression model of Parkinson’s pathology in an autophagy-dependent fashion.