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1-Methyl-4-phenylpyridinium induces synaptic dysfunction through a pathway involving caspase and PKCδ enzymatic activities
- Serulle, Yafell, Morfini, Gerardo, Pigino, Gustavo, Moreira, Jorge E., Sugimori, Mutsuyuki, Brady, Scott T., Llinás, Rodolfo R.
- Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.7 pp. 2437-2441
- Parkinson disease, action potentials, calcium, caspase-3, enzyme activity, mammals, metabolites, models, neurons, pathogenesis, peripheral nervous system diseases, protein kinase C, squid, synapse, synaptic transmission
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration has been used, in various mammalian species, as an experimental model of Parkinson's disease. The pathogenesis for such pharmacologically induced Parkinson's disease involves 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. This metabolite produces rapid degeneration of nigrostriatal dopaminergic neurons, which causes the parkinsonian syndrome. In this work, we show that injection of MPP+ into the presynaptic terminal of the squid giant synapse blocks synaptic transmission without affecting the presynaptic action potential or the presynaptic calcium currents. These effects of MPP+ were mimicked by the injection of an active form of caspase-3 and prevented by inhibitors of caspase-3 and protein kinase C δ. Ultrastructurally, MPP+-injected synapses showed a dramatic reduction in the number of neurotransmitter vesicles at the presynaptic active zone, as compared with control synapses. Otherwise, normal docking and clathrin-coated vesicles were observed, albeit at much reduced numbers. These results indicate that MPP+ acutely reduces presynaptic vesicular availability, not release, and that MPP+-induced pathogenesis results from presynaptic dysfunction that leads, secondarily, to dying-back neuropathy in affected neurons.