In this study, heterozygous expression of a common Parkinson-associated GBA1 variant, the L444P mutation, was found to exacerbate α-synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system. These neurons were also shown to become more vulnerable to oxidative and nitrative stress after L444P expression. The latter paralleled neuronal formation of reactive oxygen species and led to a pronounced accumulation of nitrated α-synuclein. A causal relationship linked mutation-induced oxidative/nitrative stress to enhanced α-synuclein aggregation and spreading that could indeed be rescued by neuronal overexpression of mitochondrial superoxide dismutase 2. Further evidence supported a key involvement of mitochondria as sources of reactive oxygen species as well as targets of oxidative and nitrative damage within L444P-expressing neurons. These findings support the conclusion that enhanced vulnerability to mitochondrial oxidative stress should be considered an important mechanism predisposing to pathology conversion in carriers of GBA1 mutations.

在这项研究中，发现一种常见的帕金森病相关 GBA1 变体 L444P 突变的杂合表达加剧了针对髓质迷走神经系统神经元的帕金森样病理小鼠模型中的α-突触核蛋白聚集和扩散。这些神经元在 L444P 表达后也变得更容易受到氧化和硝化应激的影响。后者与活性氧的神经元形成平行，并导致硝化 α-突触核蛋白的显着积累。因果关系将突变诱导的氧化/硝化应激与增强的 α-突触核蛋白聚集和扩散联系起来，这确实可以通过线粒体超氧化物歧化酶 2 的神经元过表达来挽救。进一步的证据支持线粒体作为活性氧来源以及表达 L444P 的神经元内氧化和硝化损伤的目标的关键参与。这些发现支持这样一个结论，即对线粒体氧化应激的易感性增加应被视为 GBA1 突变携带者易发生病理转化的重要机制。