Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.
J Neurosci. 2021 Jun 2;41(22):4937-4947. doi: 10.1523/JNEUROSCI.2770-20.2021. Epub 2021 Apr 23.
Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the SNc. In contrast, DA neurons in the VTA are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the NAc, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared with DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD. Environmental exposures to pesticides contribute significantly to pathologic processes that culminate in Parkinson's disease (PD). The pesticide rotenone has been used to generate a PD model that replicates key features of the illness, including dopamine neurodegeneration. To date, longstanding questions remain: are there dopamine neuron subpopulations resilient to rotenone; and if so, what are the molecular determinants of this resilience? Here we show that the subpopulation of midbrain dopaminergic neurons that express the vesicular glutamate transporter 2 (VGLUT2) are more resilient to rotenone-induced neurodegeneration. Rotenone also upregulates VGLUT2 more broadly in the midbrain, suggesting that VGLUT2 expression generally confers increased resilience to rotenone. VGLUT2 may therefore be a new target for boosting neuronal resilience to prevent toxicant-induced DA neurodegeneration in PD.
帕金森病（PD）的特征是 SNc 中的多巴胺（DA）神经元进行性丧失。相比之下，VTA 中的 DA 神经元相对免受神经退行性变的影响，但这种弹性的潜在机制仍知之甚少。最近的研究表明，囊泡谷氨酸转运体 2（VGLUT2）的表达选择性地影响中脑 DA 神经元的脆弱性。我们研究了在暴露于鱼藤酮的大鼠中，改变 DA 神经元 VGLUT2 的表达是否决定了神经元的弹性，鱼藤酮是一种线粒体复合物 I 抑制剂和 PD 的毒性模型。我们发现，表达 VGLUT2 的 VTA/SNc DA 神经元对鱼藤酮诱导的 DA 神经退行性变更具弹性。令人惊讶的是，VTA 和 SNc 中检测到 VGLUT2 表达的神经元密度增加对鱼藤酮的反应。此外，在 NAc 中，大多数表达 VGLUT2 的 DA 神经元投射的多巴胺能末梢与尾壳核/苍白球中的 DA 末梢相比，具有更大的弹性。更广泛地说，鱼藤酮诱导的 VGLUT2 表达末梢从神经退行性变中得到了整个纹状体的保护。总之，我们的数据表明，表达 VGLUT2 的 DA 神经元的一个独特亚群相对免受鱼藤酮的神经毒性。VTA 和 SNc 神经元及其投射中谷氨酸能机制的鱼藤酮诱导上调可能是更广泛的神经保护机制的一部分。这些发现为神经元弹性提供了一个新的潜在靶点，可以通过该靶点来防止 PD 中毒性诱导的 DA 神经退行性变。环境暴露于杀虫剂会显著促进导致帕金森病（PD）的病理过程。鱼藤酮已被用于生成 PD 模型，该模型复制了该疾病的关键特征，包括多巴胺神经退行性变。迄今为止，长期存在的问题仍然存在：是否存在对鱼藤酮有弹性的多巴胺神经元亚群；如果是这样，这种弹性的分子决定因素是什么？在这里，我们表明，表达囊泡谷氨酸转运体 2（VGLUT2）的中脑多巴胺能神经元亚群对鱼藤酮诱导的神经退行性变更具弹性。鱼藤酮还更广泛地上调了 midbrain 中的 VGLUT2，这表明 VGLUT2 的表达通常赋予了对鱼藤酮的更大弹性。因此，VGLUT2 可能是一个新的靶点，可以增强神经元的弹性，以防止 PD 中毒性诱导的 DA 神经退行性变。
