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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.