Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Mol Brain. 2019 Jan 18;12(1):5. doi: 10.1186/s13041-019-0426-7.
Parkinson's disease (PD) is associated with both motor and non-motor symptoms, including constipation, sensory neuropathy, depression, dementia and sleep disorder. Somatostatin (SST) is considered to be a modulator of GABAergic inhibitory transmission, and its levels are reduced in cerebrospinal fluid of PD patients. In the present study, we evaluated the changes in the expression of SST in GABAergic neurons derived from induced pluripotent stem cells (iPSCs) of PD patients. Neural cells were co-treated with the Wnt antagonist IWP-2 and Shh during neurosphere formation to induce GABA-positive forebrain interneurons. Quantitative analyses showed no significant differences, but slight decreases, in the potency of differentiation into GABAergic neurons derived from iPSCs between healthy control and patients with PARK2 mutations, who have been classified as a type of early-onset familial PD due to mutations in the parkin gene. Under this condition, the mRNA level of SST in GABAergic interneurons derived from iPSCs of PARK2-specific PD patients significantly decreased as neural maturation progressed. We also found that SST-positive GABAergic neurons were clearly reduced in GABAergic neurons derived from iPSCs of patients with PARK2 mutations. These findings suggest that the reduction in the expression level of SST in GABAergic interneurons of PD may, at least partly, lead to complex PD-induced symptoms.
帕金森病（PD）与运动和非运动症状有关，包括便秘、感觉神经病、抑郁、痴呆和睡眠障碍。生长抑素（SST）被认为是 GABA 能抑制性传递的调节剂，其在 PD 患者的脑脊液中的水平降低。在本研究中，我们评估了帕金森病患者诱导多能干细胞（iPSC）来源的 GABA 能神经元中 SST 表达的变化。神经细胞在神经球形成过程中与 Wnt 拮抗剂 IWP-2 和 Shh 共同处理，以诱导 GABA 阳性前脑中间神经元。定量分析显示，源自健康对照组和 PARK2 基因突变患者（由于 parkin 基因突变而被归类为早发性家族性 PD 类型）的 iPSC 分化为 GABA 能神经元的效力没有显著差异，但略有下降。在这种情况下，源自 PARK2 特异性 PD 患者的 iPSC 的 GABA 能中间神经元中的 SST mRNA 水平随着神经成熟的进展而显著降低。我们还发现，源自 PARK2 基因突变患者的 iPSC 的 GABA 能神经元中 SST 阳性 GABA 能神经元明显减少。这些发现表明，PD 中 GABA 能中间神经元中 SST 表达水平的降低至少部分导致了复杂的 PD 诱导症状。
