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Interplay between Cytosolic Dopamine, Calcium, and α-Synuclein Causes Selective Death of Substantia Nigra Neurons

2009; Cell Press; Volume: 62; Issue: 2 Linguagem: Inglês

10.1016/j.neuron.2009.01.033

1097-4199

Eugene V. Mosharov, Kristin E. Larsen, Ellen Kanter, Kester A. Phillips, Krystal Wilson, Yvonne Schmitz, David E. Krantz, Kazuto Kobayashi, Robert H. Edwards, David Sulzer,

Neuroscience and Neuropharmacology Research

Summary The basis for selective death of specific neuronal populations in neurodegenerative diseases remains unclear. Parkinson's disease (PD) is a synucleinopathy characterized by a preferential loss of dopaminergic neurons in the substantia nigra (SN), whereas neurons of the ventral tegmental area (VTA) are spared. Using intracellular patch electrochemistry to directly measure cytosolic dopamine (DA cyt ) in cultured midbrain neurons, we confirm that elevated DA cyt and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DA cyt provide neuroprotection. L-DOPA increased DA cyt in SN neurons to levels 2- to 3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca 2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DA cyt was not altered by α-synuclein deletion, although dopaminergic neurons lacking α-synuclein were resistant to L-DOPA-induced cell death. Thus, an interaction between Ca 2+ , DA cyt , and α-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.