Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Disorders, Beijing, China.
Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin, China.
Neurosci Lett. 2020 Jan 18;716:134640. doi: 10.1016/j.neulet.2019.134640. Epub 2019 Nov 20.
Dopaminergic (DAergic) degeneration and abnormal α-synuclein (α-syn) expression, phosphorylation and aggregation are observed in both the nigrostriatal system (NSS) and enteric nervous system (ENS) of patients with Parkinson's disease (PD). Whether these alterations in α-syn and DAergic neurons occur synchronously in the two nervous systems or follow a process that spreads from the gut to the brain remains a subject of debate. Here, in MPTP-intoxicated cynomolgus monkeys, we showed a parallel DAergic degeneration in the colon as well as in the substantia nigra and striatum (SN/STR), as indicated by reduced expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). In addition, we observed a simultaneous increase in the concentrations of total, phosphorylated, and oligomeric α-syn in the colon and SN/STR. Moreover, we identified that the above changes in α-syn were associated with an increase in the expression of polo-like kinase 2 (PLK2), an enzyme that promotes α-syn phosphorylation, and a decrease in the activity of protein phosphatase 2A (PP2A), an enzyme that facilitates α-syn dephosphorylation. Because the colonic ENS can be readily analyzed using routine biopsies, the shared pathological features between the colonic ENS and the brain NSS found in this study provide useful information for assessing and understanding the neuropathology in PD patients using colonic biopsies.
在帕金森病（PD）患者的黑质纹状体系统（NSS）和肠神经系统（ENS）中均观察到多巴胺能（DAergic）变性和异常α-突触核蛋白（α-syn）表达、磷酸化和聚集。这些α-syn 和 DAergic 神经元的改变是否在两个神经系统中同步发生，或者是否遵循从肠道传播到大脑的过程，仍然存在争议。在这里，我们在 MPTP 中毒的食蟹猴中显示，正如酪氨酸羟化酶（TH）和多巴胺转运蛋白（DAT）表达减少所表明的那样，结肠以及黑质和纹状体（SN/STR）中也存在平行的 DAergic 变性。此外，我们还观察到在结肠和 SN/STR 中总α-syn、磷酸化α-syn 和寡聚α-syn 的浓度同时增加。此外，我们确定α-syn 的上述变化与丝氨酸/苏氨酸激酶 2（PLK2）表达的增加有关，PLK2 是一种促进α-syn 磷酸化的酶，以及蛋白磷酸酶 2A（PP2A）活性的降低有关，PP2A 是一种促进α-syn 去磷酸化的酶。由于结肠 ENS 可以使用常规活检进行容易地分析，因此本研究中发现的结肠 ENS 和大脑 NSS 之间的共同病理特征为使用结肠活检评估和理解 PD 患者的神经病理学提供了有用的信息。
