Caudle W Michael, Richardson Jason R, Wang Min Z, Taylor Tonya N, Guillot Thomas S, McCormack Alison L, Colebrooke Rebecca E, Di Monte Donato A, Emson Piers C, Miller Gary W
Center for Neurodegenerative Disease, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
J Neurosci. 2007 Jul 25;27(30):8138-48. doi: 10.1523/JNEUROSCI.0319-07.2007.
The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is responsible for packaging dopamine into vesicles for subsequent release and has been suggested to serve a neuroprotective role in the dopamine system. Here, we show that mice that express approximately 5% of normal VMAT2 (VMAT2 LO) display age-associated nigrostriatal dopamine dysfunction that ultimately results in neurodegeneration. Elevated cysteinyl adducts to L-DOPA and DOPAC are seen early and are followed by increased striatal protein carbonyl and 3-nitrotyrosine formation. These changes were associated with decreased striatal dopamine and decreased expression of the dopamine transporter and tyrosine hydroxylase. Furthermore, we observed an increase in alpha-synuclein immunoreactivity and accumulation and neurodegeneration in the substantia nigra pars compacta in aged VMAT2 LO mice. Thus, VMAT2 LO animals display nigrostriatal degeneration that begins in the terminal fields and progresses to eventual loss of the cell bodies, alpha-synuclein accumulation, and an L-DOPA responsive behavioral deficit, replicating many of the key aspects of Parkinson's disease. These data suggest that mishandling of dopamine via reduced VMAT2 expression is, in and of itself, sufficient to cause dopamine-mediated toxicity and neurodegeneration in the nigrostriatal dopamine system. In addition, the altered dopamine homeostasis resulting from reduced VMAT2 function may be conducive to pathogenic mechanisms induced by genetic or environmental factors thought to be involved in Parkinson's disease.
囊泡单胺转运体2(VMAT2;SLC18A2)负责将多巴胺包装到囊泡中以便随后释放,并被认为在多巴胺系统中发挥神经保护作用。在此,我们表明表达约5%正常VMAT2的小鼠(VMAT2低表达小鼠)表现出与年龄相关的黑质纹状体多巴胺功能障碍,最终导致神经退行性变。早期可见L - DOPA和DOPAC的半胱氨酸加合物升高,随后纹状体蛋白质羰基和3 - 硝基酪氨酸形成增加。这些变化与纹状体多巴胺减少、多巴胺转运体和酪氨酸羟化酶表达降低有关。此外,我们观察到老年VMAT2低表达小鼠黑质致密部α - 突触核蛋白免疫反应性增加、积累以及神经退行性变。因此,VMAT2低表达动物表现出黑质纹状体变性,始于终末区域,进展至最终细胞体丧失、α - 突触核蛋白积累以及L - DOPA反应性行为缺陷,重现了帕金森病的许多关键特征。这些数据表明,通过降低VMAT2表达而导致的多巴胺处理不当本身足以在黑质纹状体多巴胺系统中引起多巴胺介导的毒性和神经退行性变。此外,VMAT2功能降低导致的多巴胺稳态改变可能有利于由被认为与帕金森病有关的遗传或环境因素诱导的致病机制。