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

• Published in: Neuron (Cambridge, Mass.) Vol. 62; no. 2; pp. 218 - 229
• Main Authors: Mosharov, Eugene V., Larsen, Kristin E., Kanter, Ellen, Phillips, Kester A., Wilson, Krystal, Schmitz, Yvonne, Krantz, David E., Kobayashi, Kazuto, Edwards, Robert H., Sulzer, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.04.2009
• Subjects: alpha-Synuclein - deficiency; alpha-Synuclein - metabolism; Animals; Animals, Newborn; Calbindins; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Cell Death - drug effects; Cell Death - genetics; Cytosol - drug effects; Cytosol - metabolism; Dopamine - metabolism; Dopamine Agents - pharmacology; Dose-Response Relationship, Drug; Electrochemistry - methods; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Green Fluorescent Proteins - genetics; Humans; Hydrazines - pharmacology; Levodopa - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons - cytology; Neurons - drug effects; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein G - metabolism; Substantia Nigra - cytology; Time Factors; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; Vesicular Monoamine Transport Proteins - genetics; Vesicular Monoamine Transport Proteins - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2009.01.033

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 (DAcyt) in cultured midbrain neurons, we confirm that elevated DAcyt and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DAcyt provide neuroprotection. L-DOPA increased DAcyt in SN neurons to levels 2- to 3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DAcyt 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 Ca2+, DAcyt, and α-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.