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
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Neuron. 2009 Apr 30;62(2):218-29. 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 (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.
神经退行性疾病中特定神经元群体选择性死亡的基础仍不清楚。帕金森病（PD）是一种以黑质（SN）中多巴胺能神经元优先丧失为特征的突触核蛋白病，而腹侧被盖区（VTA）的神经元则幸免于难。我们利用细胞内膜片电化学方法直接测量培养的中脑神经元中的胞质多巴胺（DA(cyt)），证实升高的DA(cyt)及其代谢产物具有神经毒性，而降低DA(cyt)的基因和药理学干预可提供神经保护作用。左旋多巴使SN神经元中的DA(cyt)升高至比VTA神经元高2至3倍的水平，这种反应依赖于对二氢吡啶敏感的Ca2+通道，导致SN神经元对左旋多巴诱导的神经毒性更敏感。尽管缺乏α-突触核蛋白的多巴胺能神经元对左旋多巴诱导的细胞死亡具有抗性，但α-突触核蛋白缺失并未改变DA(cyt)。因此，Ca2+、DA(cyt)和α-突触核蛋白之间的相互作用可能是PD中SN神经元易感性的基础，提示了多个治疗靶点。
