Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States.
ACS Chem Neurosci. 2022 Jan 19;13(2):187-193. doi: 10.1021/acschemneuro.1c00741. Epub 2022 Jan 7.
Growing evidence has established that a subset of dopamine (DA) neurons co-release glutamate and express vesicular glutamate transporter 2 (VGLUT2). VGLUT2 expression in DA neurons plays a key role in selective vulnerability to DA neurodegeneration in Parkinson's disease (PD). In this review, we summarize recent findings on impacts of VGLUT2 expression and glutamate co-release from DA neurons on selective DA neuron vulnerability. We present evidence that DA neuron VGLUT2 expression may be neuroprotective, boosting DA neuron resilience in the context of ongoing neurodegenerative processes in PD. We highlight genetic and pesticide models of PD that have provided mechanistic insights into selective DA neuron vulnerability. Finally, we discuss potential neuroprotective mechanisms, focusing on roles of VGLUT2 and glutamate in promoting mitochondrial health and diminishing oxidative stress and excitotoxicity. Elucidating these mechanisms may ultimately lead to more effective treatments to boost DA neuron resilience that can slow or even prevent DA neurodegeneration.
越来越多的证据表明，多巴胺 (DA) 神经元的亚群共同释放谷氨酸并表达囊泡谷氨酸转运体 2 (VGLUT2)。DA 神经元中的 VGLUT2 表达在帕金森病 (PD) 中对 DA 神经退行性变的选择性易感性中起着关键作用。在这篇综述中，我们总结了最近关于 VGLUT2 表达和从 DA 神经元共同释放谷氨酸对选择性 DA 神经元易感性的影响的发现。我们提供的证据表明，DA 神经元 VGLUT2 表达可能具有神经保护作用，在 PD 中持续的神经退行性过程中增强 DA 神经元的弹性。我们强调了 PD 的遗传和农药模型，这些模型为选择性 DA 神经元易感性提供了机制上的见解。最后，我们讨论了潜在的神经保护机制，重点是 VGLUT2 和谷氨酸在促进线粒体健康、减少氧化应激和兴奋性毒性方面的作用。阐明这些机制最终可能会导致更有效的治疗方法来增强 DA 神经元的弹性，从而减缓甚至预防 DA 神经退行性变。
