Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.
Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.
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DOI：
10.1002/mds.25736
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发表时间：
2014-07
影响因子：
8.6
通讯作者：
Kordower, Jeffrey H.
中科院分区：
文献类型：
--
作者：
Kelly, Leo P.;Carvey, Paul M.;Keshavarzian, Ali;Shannon, Kathleen M.;Shaikh, Maliha;Bakay, Roy A. E.;Kordower, Jeffrey H.
帕金森病（PD）是一种多灶性退行性疾病，目前尚无治愈方法。大多数病例是散发的，病因不明。最近的数据表明，未经治疗的新生PD患者结肠通透性增加，新生和运动前患者的结肠中α-突触核蛋白（α-syn）均有病理表达。这两个终点都可能作为疾病的生物标志物，甚至可能通过肠源性脂多糖（LPS）诱导的神经元损伤引发PD事件。动物模型是研究肠道在帕金森病发病机制中的潜在作用的理想方法；然而，目前很少有PD动物模型包含这些非运动特征。我们试图建立一种包括人类患者胃肠道功能障碍的PD进行性模型。C57/BL6小鼠系统给予LPS （2.5 mg/kg）或生理盐水一剂，按月间隔（n=5只，连续5个月）处死，形成一个时间过程。采用毛细管柱气相色谱法分析口服糖探针尿量，评价小肠和大肠通透性。通过计数整个胃肠道中轻度、中度和重度受影响的肌肠神经节神经元的数量来评估α-Syn的表达，并通过定量光密度测量来验证计数。采用酪氨酸羟化酶免疫组化立体学和密度测定法评估黑质纹状体的完整性。LPS在大肠中引起α-syn表达的立即和进行性增加，而在小肠中没有。LPS给药后2 - 4个月，全肠（大肠和小肠）的肠通透性逐渐增加，但在第5个月恢复到基线水平。选择性测量表明，小肠的肠通透性基本保持完整，表明肠道渗漏主要发生在大肠。在4个月和5个月时，在结肠肌肠神经元亚群中发现磷酸化丝氨酸129-α-syn。虽然这些变化是在没有黑质纹状体变性的情况下观察到的，但观察到脑干α-syn的突然但不显著的增加与通透性的恢复平行。随着时间的推移，对照组没有观察到任何变化。LPS是一种用于模拟PD的内毒素，它引起α-syn免疫反应性、肠通透性和结肠中病理性α-syn积累的顺序增加，其方式与PD患者相似。这些特征在没有黑质纹状体变性的情况下观察到，并在运动综合征之前合并了PD特征。这使得该模型有可能用于测试神经保护和疾病改善疗法，包括以肠道为导向的强化肠屏障完整性的疗法。
Parkinson’s disease (PD) is a multifocal degenerative disorder for which there is no cure. The majority of cases are sporadic with unknown etiology. Recent data indicate that untreated patients with de novo PD have increased colonic permeability and that both de novo and premotor patients have pathological expression of α-synuclein (α-syn) in their colon. Both endpoints potentially can serve as disease biomarkers and even may initiate PD events through gut-derived, lipopolysaccharide (LPS)-induced neuronal injury. Animal models could be ideal for interrogating the potential role of the intestines in the pathogenesis of PD; however, few current animal models of PD encompass these nonmotor features. We sought to establish a progressive model of PD that includes the gastrointestinal (GI) dysfunction present in human patients. C57/BL6 mice were systemically administered one dose of either LPS (2.5 mg/kg) or saline and were sacrificed in monthly intervals (n=5 mice for 5 months) to create a time-course. Small and large intestinal permeability was assessed by analyzing the urinary output of orally ingested sugar probes through capillary column gas chromatography. α-Syn expression was assessed by counting the number of mildly, moderately, and severely affected myenteric ganglia neurons throughout the GI tract, and the counts were validated by quantitative optical density measurements. Nigrostriatal integrity was assessed by tyrosine hydroxylase immunohistochemistry stereology and densitometry. LPS caused an immediate and progressive increase in α-syn expression in the large intestine but not in the small intestine. Intestinal permeability of the whole gut (large and small intestines) progressively increased between months 2 and 4 after LPS administration but returned to baseline levels at month 5. Selective measurements demonstrated that intestinal permeability in the small intestine remained largely intact, suggesting that gut leakiness was predominately in the large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity.
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DOI：
10.1016/j.alcohol.2008.12.009
发表时间：
2009-03
期刊：
Alcohol (Fayetteville, N.Y.)
影响因子：
--
作者：
Forsyth CB;Farhadi A;Jakate SM;Tang Y;Shaikh M;Keshavarzian A
通讯作者：
Keshavarzian A
影响因子：
6.1
作者：
Hallett PJ;McLean JR;Kartunen A;Langston JW;Isacson O
通讯作者：
Isacson O
影响因子：
56.9
作者：
Gill, Steven R.;Pop, Mihai;Nelson, Karen E.
通讯作者：
Nelson, Karen E.
影响因子：
6.1
作者：
Chu, Yaping;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
影响因子：
9.9
作者：
Abbott, RD;Petrovitch, H;Ross, GW
通讯作者：
Ross, GW