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.

中文翻译：

---

VGLUT2在中脑多巴胺神经元选择性脆弱中的作用

帕金森氏病的特征是黑质致密部（SNc）中多巴胺（DA）神经元的丢失。尽管对于选择性抵抗或脆弱性的机制仍知之甚少，但腹侧被盖区的DA神经元对这种变性的抵抗力比SNc中的要好。阐明这些过程的关键可能在于共释放谷氨酸并表达囊泡谷氨酸转运蛋白VGLUT2的DA神经元子集中。在这里，我们通过在果蝇和小鼠的DA神经元中过表达VGLUT解决了VGLUT表达与DA神经元易损性之间的潜在关系。在果蝇中，VGLUT的过表达导致所选DA神经元群体的丢失。类似地，VGLUT2在鼠SNc DA神经元中的特异性表达导致神经元丢失和帕金森氏症行为。其他神经元细胞类型没有显示出这种敏感性，这表明DA神经元特别容易受到VGLUT2表达的伤害。另外，大多数DA神经元在发育过程中表达VGLUT2，并且在成年人受伤后，VGLUT2与DA标志物的共表达增加。最后，VGLUT2的条件缺失使DA神经元更易受帕金森氏神经毒素的影响。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，对该VGLUT2依赖性过程的操纵可能代表了治疗性发展的途径。