Bagnoli Enrico, Trotier Alexandre, McMahon Jill, Quinlan Leo R, Biggs Manus, Pandit Abhay, FitzGerald Una
CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland.
Galway Neuroscience Centre, University of Galway, Galway, Ireland.
FASEB J. 2023 Dec;37(12):e23272. doi: 10.1096/fj.202301253R.
Parkinson's disease (PD) is a progressive, neurodegenerative disorder with an increasing incidence, unknown etiology, and is currently incurable. Advances in understanding the pathological mechanisms at a molecular level have been slow, with little attention focused on the early prodromal phase of the disease. Consequently, the development of early-acting disease-modifying therapies has been hindered. The olfactory bulb (OB), the brain region responsible for initial processing of olfactory information, is particularly affected early in PD at both functional and molecular levels but there is little information on how the cells in this region are affected by disease. Organotypic and primary OB cultures were developed and characterized. These platforms were then used to assess the effects of 3,4-dihydroxyphenylacetylaldehyde (DOPAL), a metabolite of dopamine present in increased levels in post-mortem PD tissue and which is thought to contribute to PD pathogenesis. Our findings showed that DOPAL exposure can recapitulate many aspects of PD pathology. Oxidative stress, depolarization of mitochondrial membranes, and neurodegeneration were all induced by DOPAL addition, as were measured transcriptomic changes consistent with those reported in PD clinical studies. These olfactory models of prodromal disease lend credence to the catecholaldehyde hypothesis of PD and provide insight into the mechanisms by which the OB may be involved in disease progression.
帕金森病（PD）是一种进行性神经退行性疾病，发病率不断上升，病因不明，目前无法治愈。在分子水平上对其病理机制的理解进展缓慢，很少有研究关注该疾病的早期前驱阶段。因此，早期起效的疾病修饰疗法的开发受到了阻碍。嗅球（OB）是负责嗅觉信息初始处理的脑区，在帕金森病早期，其功能和分子水平均受到特别影响，但关于该区域细胞如何受疾病影响的信息却很少。我们开发并表征了器官型和原代嗅球培养物。然后利用这些平台评估3,4 -二羟基苯乙醛（DOPAL）的作用，DOPAL是多巴胺的一种代谢产物，在帕金森病患者死后组织中的含量升高，被认为与帕金森病的发病机制有关。我们的研究结果表明，暴露于DOPAL可重现帕金森病病理的许多方面。添加DOPAL可诱导氧化应激、线粒体膜去极化和神经退行性变，同时还能检测到与帕金森病临床研究报告一致的转录组变化。这些前驱疾病的嗅觉模型为帕金森病的儿茶酚醛假说提供了支持，并深入了解了嗅球可能参与疾病进展的机制。
