Paradoxically, cigarette smoking is associated with a reduced risk of Parkinson’s Disease (PD). This led us to hypothesize that carbon monoxide (CO) levels, which are constitutively but modestly elevated in smokers, might contribute to neuroprotection. Using rodent models of PD based on α-synuclein (αSyn) accumulation and oxidative stress, we show that low-dose CO mitigates neurodegeneration and reduces αSyn pathology. Oral CO administration activated signaling cascades mediated by heme oxygenase-1 (HO-1), which have been implicated in limiting oxidative stress, and in promoting αSyn degradation, thereby conferring neuroprotection. Consistent with the neuroprotective effect of smoking, HO-1 levels in cerebrospinal fluid were higher in human smokers compared to nonsmokers. Moreover, in PD brain samples, HO-1 levels were higher in neurons without αSyn pathology. Thus, CO in rodent PD models reduces pathology and increases oxidative stress responses, phenocopying possible protective effects of smoking evident in PD patients. These data highlight the potential for low-dose CO-modulated pathways to slow symptom onset and limit pathology in PD patients.

矛盾的是，吸烟与帕金森病 (PD) 风险降低有关。这使我们推测，吸烟者中一氧化碳（CO）水平持续但适度升高，可能有助于神经保护。使用基于 α-突触核蛋白 (αSyn) 积累和氧化应激的 PD 啮齿动物模型，我们发现低剂量 CO 可以减轻神经退行性变并减少 αSyn 病理。口服 CO 可激活血红素加氧酶-1 (HO-1) 介导的信号级联，这与限制氧化应激和促进 αSyn 降解有关，从而起到神经保护作用。与吸烟的神经保护作用一致，吸烟者脑脊液中 HO-1 水平高于不吸烟者。此外，在 PD 大脑样本中，没有 αSyn 病理的神经元中 HO-1 水平较高。因此，啮齿动物帕金森病模型中的一氧化碳可减轻病理并增加氧化应激反应，表型复制吸烟对帕金森病患者可能产生的保护作用。这些数据强调了低剂量 CO 调节途径减缓 PD 患者症状发作和限制病理的潜力。