Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons.
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.
Mosharov
Eugene V
EV
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Larsen
Kristin E
KE
Kanter
Ellen
E
Phillips
Kester A
KA
Wilson
Krystal
K
Schmitz
Yvonne
Y
Krantz
David E
DE
Kobayashi
Kazuto
K
Edwards
Robert H
RH
Sulzer
David
D
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*
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