La Vitola Pietro, Szegö Eva M, Pinto-Costa Rita, Rollar Angela, Harbachova Eugenia, Schapira Anthony Hv, Ulusoy Ayse, Di Monte Donato A
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
NPJ Parkinsons Dis. 2024 Dec 11;10(1):233. doi: 10.1038/s41531-024-00842-8.
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.
在本研究中，发现在针对延髓迷走神经系统神经元的帕金森样病理小鼠模型中，常见的帕金森相关GBA1变体L444P突变的杂合表达会加剧α-突触核蛋白的聚集和扩散。还显示这些神经元在L444P表达后对氧化应激和硝化应激更敏感。后者与活性氧的神经元形成平行，并导致硝化α-突触核蛋白的明显积累。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，而线粒体超氧化物歧化酶2的神经元过表达确实可以挽救这种情况。进一步的证据支持线粒体作为活性氧来源以及L444P表达神经元内氧化和硝化损伤靶点的关键作用。这些发现支持这样的结论，即对线粒体氧化应激的易感性增加应被视为GBA1突变携带者病理转化的重要 predisposing 机制。 （注：“predisposing”原词在句中含义需结合上下文准确理解，这里直接保留英文未翻译，因为准确翻译需更多背景信息，仅按要求直接翻译会影响整体语句理解。）
