title: Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons.
abstract: 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 Ca2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DA(cyt) was not altered by alpha-synuclein deletion, although dopaminergic neurons lacking alpha-synuclein were resistant to L-DOPA-induced cell death. Thus, an interaction between Ca2+, DA(cyt), and alpha-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Mosharov
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Larsen
authors.forename: Ellen
authors.initials: E
authors.lastname: Kanter
authors.forename: Kester A
authors.initials: KA
authors.lastname: Phillips
authors.forename: Krystal
authors.initials: K
authors.lastname: Wilson
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schmitz
authors.forename: David E
authors.initials: DE
authors.lastname: Krantz
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000172:deficiency / Q000378:metabolism*
chemical_list: D064026:Calbindins; D002121:Calcium Channel Blockers; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D006834:Hydrazines; D064030:S100 Calcium Binding Protein G; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D007980:Levodopa; C004297:3-hydroxybenzylhydrazine; D014446:Tyrosine 3-Monooxygenase; D002118:Calcium; D004298:Dopamine