Rose K N, Zorlu M, Fassini A, Lee H, Cai W, Xue X, Lin S, Kivisakk P, Schwarzschild M A, Chen X, Gomperts S N
Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Harvard Medical School, Boston, MA, 02115, USA.
NPJ Parkinsons Dis. 2024 Aug 22;10(1):152. doi: 10.1038/s41531-024-00763-6.
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，吸烟者体内持续但适度升高的一氧化碳（CO）水平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可减轻神经退行性变并减少αSyn病理变化。口服CO激活了由血红素加氧酶-1（HO-1）介导的信号级联反应，这与限制氧化应激和促进αSyn降解有关，从而赋予神经保护作用。与吸烟的神经保护作用一致，人类吸烟者脑脊液中的HO-1水平高于不吸烟者。此外，在PD脑样本中，无αSyn病理变化的神经元中HO-1水平更高。因此，啮齿动物PD模型中的CO可减少病理变化并增加氧化应激反应，模拟了PD患者中吸烟可能具有的保护作用。这些数据突出了低剂量CO调节通路减缓PD患者症状发作和限制病理变化的潜力。
