Emerging findings suggest that Parkinson’s disease (PD) pathology (α-synuclein accumulation) and neuronal dysfunction may occur first in peripheral neurons of the autonomic nervous system including the enteric branches of the vagus nerve. The risk of PD increases greatly in people over the age of 65, a period of life in which chronic inflammation is common in many organ systems including the gut. Here we report that chronic mild focal intestinal inflammation accelerates the age of disease onset in α-synuclein mutant PD mice. Wild-type and PD mice treated with 0.5% dextran sodium sulfate (DSS) in their drinking water for 12 weeks beginning at 3 months of age exhibited histological and biochemical features of mild gut inflammation. The age of onset of motor dysfunction, evaluated using a rotarod test, gait analysis, and grip strength measurements, was significantly earlier in DSS-treated PD mice compared to control PD mice. Levels of the dopaminergic neuron marker tyrosine hydroxylase in the striatum and numbers of dopaminergic neurons in the substantia nigra were reduced in PD mice with gut inflammation. Levels of total and phosphorylated α-synuclein were elevated in enteric and brain neurons in DSS-treated PD mice, suggesting that mild gut inflammation accelerates α-synuclein pathology. Markers of inflammation in the colon and brain, but not in the blood, were elevated in DSS-treated PD mice, consistent with retrograde transneuronal propagation of α-synuclein pathology and neuroinflammation from the gut to the brain. Our findings suggest that interventions that reduce gut inflammation may prove beneficial in the prevention and treatment of PD.

中文翻译：

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慢性轻度肠道炎症会加速 α-突触核蛋白突变小鼠的脑神经病理学和运动功能障碍。

新发现表明，帕金森病 (PD) 病理学（α-突触核蛋白积累）和神经元功能障碍可能首先发生在自主神经系统的周围神经元中，包括迷走神经的肠分支。65 岁以上的人患 PD 的风险大大增加，在这个年龄段，慢性炎症在包括肠道在内的许多器官系统中都很常见。在此，我们报道慢性轻度局灶性肠道炎症会加速 α-突触核蛋白突变 PD 小鼠的发病年龄。从 3 个月大开始，用含 0.5% 葡聚糖硫酸钠 (DSS) 的饮用水处理野生型和 PD 小鼠 12 周，表现出轻度肠道炎症的组织学和生化特征。通过旋转棒测试、步态分析和握力测量评估，DSS 治疗的 PD 小鼠运动功能障碍的发病年龄明显早于对照 PD 小鼠。在患有肠道炎症的 PD 小鼠中，纹状体中多巴胺能神经元标记物酪氨酸羟化酶的水平和黑质中多巴胺能神经元的数量减少。DSS 治疗的 PD 小鼠肠道和脑神经元中总 α-突触核蛋白和磷酸化 α-突触核蛋白水平升高，表明轻度肠道炎症加速 α-突触核蛋白病理。在 DSS 治疗的 PD 小鼠中，结肠和大脑中的炎症标志物升高，但血液中的炎症标志物没有升高，这与 α-突触核蛋白病理学的逆行跨神经元传播和从肠道到大脑的神经炎症一致。我们的研究结果表明，减少肠道炎症的干预措施可能有益于预防和治疗帕金森病。