Savolainen Mari H, Albert Katrina, Airavaara Mikko, Myöhänen Timo T
Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Exp Brain Res. 2017 Jul;235(7):2189-2202. doi: 10.1007/s00221-017-4962-z. Epub 2017 Apr 24.
Proteinaceous inclusions, called Lewy bodies, are used as a pathological hallmark for Parkinson's disease (PD). Lewy bodies contain insoluble α-synuclein (aSyn) and many other ubiquitinated proteins, suggesting a role for protein degradation system failure in the PD pathogenesis. Indeed, proteasomal dysfunction has been linked to PD but commonly used in vivo toxin models, such as 6-OHDA or MPTP, do not have a significant effect on the proteasomal system or protein aggregation. Therefore, we wanted to study the characteristics of a proteasomal inhibitor, lactacystin, as a PD model on young and adult mice. To study this, we performed stereotactic microinjection of lactacystin above the substantia nigra pars compacta in young (2 month old) and adult (12-14 month old) C57Bl/6 mice. Motor behavior was measured by locomotor activity and cylinder tests, and the markers of neuroinflammation, aSyn, and dopaminergic system were assessed by immunohistochemistry and HPLC. We found that lactacystin induced a Parkinson's disease-like motor phenotype 5-7 days after injection in young and adult mice, and this was associated with widespread neuroinflammation based on glial cell markers, aSyn accumulation in substantia nigra, striatal dopamine decrease, and loss of dopaminergic cell bodies in the substantia nigra and terminals in the striatum. When comparing young and adult mice, adult mice were more sensitive for dopaminergic degeneration after lactacystin injection that further supports the use of adult mice instead of young when modeling neurodegeneration. Our data showed that lactacystin is useful in modeling various aspects of Parkinson's disease, and taken together, our findings emphasize the role of a protein degradation deficit in Parkinson's disease pathology, and support the use of proteasomal inhibitors as Parkinson's disease models.
称为路易小体的蛋白质内含物被用作帕金森病（PD）的病理标志。路易小体包含不溶性α-突触核蛋白（aSyn）和许多其他泛素化蛋白，这表明蛋白质降解系统功能障碍在PD发病机制中起作用。事实上，蛋白酶体功能障碍与PD有关，但常用的体内毒素模型，如6-羟基多巴胺（6-OHDA）或1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），对蛋白酶体系统或蛋白质聚集没有显著影响。因此，我们想研究蛋白酶体抑制剂乳胞素作为年轻和成年小鼠PD模型的特征。为了研究这一点，我们对年轻（2个月大）和成年（12 - 14个月大）的C57Bl/6小鼠在黑质致密部上方进行了乳胞素的立体定向显微注射。通过运动活动和圆筒试验测量运动行为，并通过免疫组织化学和高效液相色谱法评估神经炎症、aSyn和多巴胺能系统的标志物。我们发现，乳胞素在年轻和成年小鼠注射后5 - 7天诱导出帕金森病样运动表型，这与基于胶质细胞标志物的广泛神经炎症、黑质中aSyn积累、纹状体多巴胺减少以及黑质中多巴胺能细胞体和纹状体终末的丧失有关。比较年轻和成年小鼠时，成年小鼠在注射乳胞素后对多巴胺能变性更敏感，这进一步支持在模拟神经退行性变时使用成年小鼠而非年轻小鼠。我们的数据表明，乳胞素可用于模拟帕金森病的各个方面，总体而言，我们的研究结果强调了蛋白质降解缺陷在帕金森病病理学中的作用，并支持使用蛋白酶体抑制剂作为帕金森病模型。
