Department of Neurosciences, UCSD, La Jolla, California, USA.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Clin Invest. 2018 Feb 1;128(2):774-788. doi: 10.1172/JCI95795. Epub 2018 Jan 16.
Parkinson's disease is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DA neurons in the ventral tegmental area are more resistant to this degeneration than those in the SNc, though the mechanisms for selective resistance or vulnerability remain poorly understood. A key to elucidating these processes may lie within the subset of DA neurons that corelease glutamate and express the vesicular glutamate transporter VGLUT2. Here, we addressed the potential relationship between VGLUT expression and DA neuronal vulnerability by overexpressing VGLUT in DA neurons of flies and mice. In Drosophila, VGLUT overexpression led to loss of select DA neuron populations. Similarly, expression of VGLUT2 specifically in murine SNc DA neurons led to neuronal loss and Parkinsonian behaviors. Other neuronal cell types showed no such sensitivity, suggesting that DA neurons are distinctively vulnerable to VGLUT2 expression. Additionally, most DA neurons expressed VGLUT2 during development, and coexpression of VGLUT2 with DA markers increased following injury in the adult. Finally, conditional deletion of VGLUT2 made DA neurons more susceptible to Parkinsonian neurotoxins. These data suggest that the balance of VGLUT2 expression is a crucial determinant of DA neuron survival. Ultimately, manipulation of this VGLUT2-dependent process may represent an avenue for therapeutic development.
帕金森病的特征是黑质致密部（SNc）中的多巴胺（DA）神经元丧失。腹侧被盖区（VTA）中的 DA 神经元比 SNc 中的神经元更能抵抗这种退化，尽管选择性抵抗或易感性的机制仍知之甚少。阐明这些过程的关键可能在于同时释放谷氨酸并表达囊泡谷氨酸转运体 VGLUT2 的 DA 神经元亚群中。在这里，我们通过在果蝇和小鼠的 DA 神经元中过表达 VGLUT 来研究 VGLUT 表达与 DA 神经元易感性之间的潜在关系。在果蝇中，VGLUT 的过表达导致了部分 DA 神经元群体的丧失。同样，VGLUT2 特异性在小鼠 SNc DA 神经元中的表达导致了神经元丧失和帕金森样行为。其他神经元类型没有表现出这种敏感性，这表明 DA 神经元对 VGLUT2 表达特别敏感。此外，大多数 DA 神经元在发育过程中表达 VGLUT2，并且在成年后的损伤后，VGLUT2 与 DA 标志物的共表达增加。最后，VGLUT2 的条件缺失使 DA 神经元更容易受到帕金森神经毒素的影响。这些数据表明，VGLUT2 表达的平衡是 DA 神经元存活的关键决定因素。最终，对这种 VGLUT2 依赖性过程的操纵可能代表一种治疗开发的途径。
