Maingay Matthew, Romero-Ramos Marina, Carta Manolo, Kirik Deniz
Department of Experimental Medical Science, Section of Neuroscience, CNS Disease Modeling Unit, Lund University, Wallenberg Neuroscience Center, BMCA11, S-22184 Lund, Sweden.
Neurobiol Dis. 2006 Sep;23(3):522-32. doi: 10.1016/j.nbd.2006.04.007. Epub 2006 Jun 30.
Parkinson's disease (PD) is characterized by the formation of intracytoplasmic inclusions, which contain alpha-synuclein (alpha-syn) protein. While most profound neurodegeneration is seen in the dopamine (DA) synthesizing neurons located in the ventral midbrain, it is unclear why some DA cell groups are more susceptible than others. In the midbrain, the degeneration of the substantia nigra (SN) DA neurons is severe, whereas the involvement of the ventral tegmental area (VTA) neurons is relatively spared. In the present study, we overexpressed human A53T alpha-syn in the VTA neurons and found that A53T toxicity did not affect their survival. There was, however, a mild functional impairment seen as altered open field locomotor activity. Overexpression of A53T in the SN, on the other hand, led to profound cell loss. These results suggest that the selective susceptibility of nigral DA neurons is at least in part associated with factor(s) involved in handling of alpha-syn that is not shared by the VTA neurons. Secondly, these results highlight the fact that impaired but surviving neurons can have a substantial impact on DA-dependent behavior and should therefore be considered as a critical part of animal models where novel therapeutic interventions are tested.
帕金森病（PD）的特征是形成包含α-突触核蛋白（α-syn）的胞质内包涵体。虽然在位于腹侧中脑的多巴胺（DA）合成神经元中可见最严重的神经退行性变，但尚不清楚为何某些DA细胞群比其他细胞群更易受影响。在中脑中，黑质（SN）的DA神经元变性严重，而腹侧被盖区（VTA）神经元的受累相对较轻。在本研究中，我们在VTA神经元中过表达人A53Tα-syn，发现A53T毒性并不影响它们的存活。然而，观察到有轻微的功能损害，表现为旷场运动活动改变。另一方面，在SN中过表达A53T则导致大量细胞丢失。这些结果表明，黑质DA神经元的选择性易感性至少部分与VTA神经元所不具备的参与处理α-syn的因子有关。其次，这些结果突出了这样一个事实，即受损但存活的神经元可对DA依赖行为产生重大影响，因此在测试新型治疗干预措施的动物模型中应将其视为关键部分。
