CNS Disease Research, Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riss, Germany.
J Neuropathol Exp Neurol. 2018 Jun 1;77(6):443-453. doi: 10.1093/jnen/nly024.
Increasing evidence suggests a relationship between oxidative stress and α-synuclein aggregation, the primary pathological hallmark of Parkinson disease (PD). However, a direct causal relationship has not yet been established in vivo in mouse models of PD. Superoxide dismutase 2 (SOD2) is rate limiting in the antioxidant machinery of the mitochondria and even its partial deficiency elevates oxidative stress in mice. Therefore, in order to investigate a possible interaction between oxidative stress and α-synuclein aggregation in vivo, a transgenic model of PD with haplodeficiency for SOD2 was generated on the basis of the well-characterized murine (Thy-1)-h[A30P]-α-synuclein transgenic line. In comparison with littermate controls with full SOD2 capacity, α-synuclein transgenic mice with partial SOD2 deficiency exhibited a significantly more advanced stage of synucleinopathy at 16 months, as demonstrated by higher median PK-PET blot scores (p < 0.01) and a greater amount of truncated α-synuclein in the insoluble fraction of homogenized brains (p < 0.05). These results show that compromising the capacity to scavenge free radicals can exacerbate α-synuclein aggregation, indicating that elevated levels of oxidative stress could modulate the progression of PD.
越来越多的证据表明氧化应激与α-突触核蛋白聚集之间存在关系，α-突触核蛋白聚集是帕金森病 (PD) 的主要病理标志。然而，在 PD 的小鼠模型中，尚未在体内建立直接的因果关系。超氧化物歧化酶 2 (SOD2) 是线粒体抗氧化机制中的限速酶，即使其部分缺乏也会使小鼠的氧化应激升高。因此，为了在体内研究氧化应激与α-突触核蛋白聚集之间的可能相互作用，在经过充分表征的鼠 (Thy-1)-h[A30P]-α-突触核蛋白转基因系的基础上，生成了 SOD2 单倍体缺陷的 PD 转基因模型。与具有完整 SOD2 能力的同窝对照相比，部分 SOD2 缺乏的α-突触核蛋白转基因小鼠在 16 个月时表现出更先进的突触核蛋白病阶段，这表现为 PK-PET 印迹评分更高（p<0.01）和匀浆脑的不溶性部分中截短的α-突触核蛋白量更大（p<0.05）。这些结果表明，自由基清除能力受损会加剧α-突触核蛋白聚集，表明氧化应激水平升高可能会调节 PD 的进展。
