Davis Jacinta, Kolaski Elizabeth, Babcock Daniel T
Department of Biological Sciences, Lehigh University, Bethlehem, PA, USA.
NPJ Parkinsons Dis. 2022 Nov 2;8(1):147. doi: 10.1038/s41531-022-00417-5.
The hallmark of Parkinson's disease (PD) is the loss of dopaminergic (DA) neurons in the brain. However, little is known about why DA neurons are selectively vulnerable to PD. We previously completed a screen identifying genes associated with the progressive degeneration of DA neurons. Here we describe the role of a previously uncharacterized gene, CG42339, in the loss of DA neurons using Drosophila Melanogaster. CG42339 mutants display a progressive loss of DA neurons and locomotor dysfunction, along with an accumulation of advanced glycation end products (AGEs) in the brain. Based on this phenotype, we refer to CG42339 as vexed. We demonstrate that vexed is specifically required within cortex glia to maintain neuronal viability. Loss of vexed function results in excessive activation of the innate immune response in the brain, leading to loss of DA neurons. We show that activation of the innate immune response leads to increased nitric oxide signaling and accumulation of AGEs, which ultimately result in neurodegeneration. These results provide further insight into the relationship between the role of the immune response in the central nervous system and how this impacts neuronal viability.
帕金森病（PD）的标志是大脑中多巴胺能（DA）神经元的丧失。然而，关于DA神经元为何对PD具有选择性易损性，人们了解甚少。我们之前完成了一项筛选，确定了与DA神经元进行性退化相关的基因。在此，我们利用黑腹果蝇描述了一个此前未被鉴定的基因CG42339在DA神经元丧失中的作用。CG42339突变体表现出DA神经元的进行性丧失和运动功能障碍，同时大脑中晚期糖基化终产物（AGEs）积累。基于这种表型，我们将CG42339称为“烦恼”（vexed）。我们证明，在皮质神经胶质细胞中，“烦恼”对于维持神经元的活力是特别必需的。“烦恼”功能的丧失会导致大脑中固有免疫反应过度激活，从而导致DA神经元丧失。我们表明，固有免疫反应的激活会导致一氧化氮信号增强和AGEs积累，最终导致神经退行性变。这些结果为深入了解中枢神经系统中免疫反应的作用与这如何影响神经元活力之间的关系提供了进一步的见解。
