Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
Neurosci Lett. 2023 Nov 1;816:137510. doi: 10.1016/j.neulet.2023.137510. Epub 2023 Oct 5.
Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopamine (DA) neurons and the presence of alpha-synuclein (αSyn)-positive Lewy body (LB) pathology. In this study, we attempted to recapitulate both these features in a novel in vitro model for PD. To achieve this, we combined the αSyn pre-formed fibril (PFF)-seeded LB-like pathology with 6-hydroxydopamine (6-OHDA)-induced mitochondrial toxicity in mouse embryonic midbrain cultures. To pilot the model for therapeutics testing, we assessed the effects of cerebral dopamine neurotrophic factor (CDNF) on αSyn aggregation and neuron survival. PFF-seeded pathology did not lead to DA neuron loss even with the highest dose of PFFs. The combination of PFFs and 6-OHDA did not trigger additional neurodegeneration or LB-like pathology and instead presented DA neuron loss to a similar extent as with 6-OHDA only. CDNF did not affect the PFF-seeded αSyn pathology or the DA neuron survival in the combination model but showed a trend toward neuroprotection in the 6-OHDA-only cultures.
帕金森病（PD）的特征是黑质纹状体多巴胺（DA）神经元的丧失和α-突触核蛋白（αSyn）阳性路易体（LB）病理学的存在。在这项研究中，我们试图在一种新的 PD 体外模型中重现这两种特征。为此，我们将αSyn 预形成纤维（PFF）引发的 LB 样病理学与 6-羟基多巴胺（6-OHDA）诱导的线粒体毒性结合在一起来进行研究。为了对该模型进行治疗测试，我们评估了脑多巴胺神经营养因子（CDNF）对αSyn 聚集和神经元存活的影响。即使使用最高剂量的 PFF，PFF 引发的病理学也不会导致 DA 神经元丧失。PFF 与 6-OHDA 的组合并没有引发额外的神经退行性变或 LB 样病理学，而是与仅用 6-OHDA 处理的情况一样导致 DA 神经元丧失。CDNF 对 PFF 引发的αSyn 病理学或组合模型中的 DA 神经元存活没有影响，但在仅用 6-OHDA 处理的培养物中显示出神经保护的趋势。
