Kanaan N M, Kordower J H, Collier T J
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Eur J Neurosci. 2008 Jun;27(12):3205-15. doi: 10.1111/j.1460-9568.2008.06307.x.
Aging is the strongest risk factor for developing Parkinson's disease (PD). There is a preferential loss of dopamine (DA) neurons in the ventral tier of the substantia nigra (vtSN) compared to the dorsal tier and ventral tegmental area (VTA) in PD. Examining age-related and region-specific differences in DA neurons represents a means of identifying factors potentially involved in vulnerability or resistance to degeneration. Nitrative stress is among the factors potentially underlying DA neuron degeneration. We studied the relationship between 3-nitrotyrosine (3NT; a marker of nitrative damage) and DA transporters [DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT)] during aging in DA subregions of rhesus monkeys. The percentage of DA neurons containing 3NT increased significantly only in the vtSN with advancing age, and the vtSN had a greater percentage of 3NT-positive neurons when compared to the VTA. The relationship between 3NT and DA transporters was determined by measuring fluorescence intensity of 3NT, DAT and VMAT staining. 3NT intensity increased with advancing age in the vtSN. Increased DAT, VMAT and DAT/VMAT ratios were associated with increased 3NT in individual DA neurons. These results suggest nitrative damage accumulates in midbrain DA neurons with advancing age, an effect exacerbated in the vulnerable vtSN. The capacity of a DA neuron to accumulate more cytosolic DA, as inferred from DA transporter expression, is related to accumulation of nitrative damage. These findings are consistent with a role for aging-related accrual of nitrative damage in the selective vulnerability of vtSN neurons to degeneration in PD.
衰老是患帕金森病（PD）的最强风险因素。与黑质背侧层和腹侧被盖区（VTA）相比，PD患者中脑黑质腹侧层（vtSN）的多巴胺（DA）神经元有优先损失。研究DA神经元中与年龄相关的和区域特异性差异，是识别可能参与神经元易损性或抗变性的因素的一种方法。硝化应激是DA神经元变性潜在的因素之一。我们研究了恒河猴DA亚区衰老过程中3-硝基酪氨酸（3NT；硝化损伤的标志物）与DA转运体[DA转运体（DAT）和囊泡单胺转运体2（VMAT）]之间的关系。随着年龄增长，仅vtSN中含3NT的DA神经元百分比显著增加，且与VTA相比，vtSN中3NT阳性神经元的百分比更高。通过测量3NT、DAT和VMAT染色的荧光强度来确定3NT与DA转运体之间的关系。vtSN中3NT强度随年龄增长而增加。单个DA神经元中，DAT、VMAT增加以及DAT/VMAT比值增加与3NT增加相关。这些结果表明，随着年龄增长，中脑DA神经元中硝化损伤会累积，在易损的vtSN中这种影响会加剧。从DA转运体表达推断，DA神经元积累更多胞质DA的能力与硝化损伤的积累有关。这些发现与衰老相关的硝化损伤积累在PD中vtSN神经元选择性易损性变性中所起的作用一致。
