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纹状体谷胱甘肽-抗坏血酸代谢受损导致多巴胺短暂增加和运动功能障碍。

Impaired striatal glutathione-ascorbate metabolism induces transient dopamine increase and motor dysfunction.

机构信息

Department of Pharmacology, University of Oxford, Oxford, UK.

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford and John Radcliffe Hospital, Oxford, UK.

出版信息

Nat Metab. 2024 Nov;6(11):2100-2117. doi: 10.1038/s42255-024-01155-z. Epub 2024 Oct 28.

DOI:10.1038/s42255-024-01155-z
PMID:39468205
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11599059/
Abstract

Identifying initial triggering events in neurodegenerative disorders is critical to developing preventive therapies. In Huntington's disease (HD), hyperdopaminergia-probably triggered by the dysfunction of the most affected neurons, indirect pathway spiny projection neurons (iSPNs)-is believed to induce hyperkinesia, an early stage HD symptom. However, how this change arises and contributes to HD pathogenesis is unclear. Here, we demonstrate that genetic disruption of iSPNs function by Ntrk2/Trkb deletion in mice results in increased striatal dopamine and midbrain dopaminergic neurons, preceding hyperkinetic dysfunction. Transcriptomic analysis of iSPNs at the pre-symptomatic stage showed de-regulation of metabolic pathways, including upregulation of Gsto2, encoding glutathione S-transferase omega-2 (GSTO2). Selectively reducing Gsto2 in iSPNs in vivo effectively prevented dopaminergic dysfunction and halted the onset and progression of hyperkinetic symptoms. This study uncovers a functional link between altered iSPN BDNF-TrkB signalling, glutathione-ascorbate metabolism and hyperdopaminergic state, underscoring the vital role of GSTO2 in maintaining dopamine balance.

摘要

确定神经退行性疾病的初始触发事件对于开发预防疗法至关重要。在亨廷顿病（HD）中，多巴胺能亢进-可能由受影响最严重的神经元功能障碍引起-间接通路棘突投射神经元（iSPN）被认为会引发运动过度，这是 HD 的早期症状。然而，这种变化是如何产生的以及如何导致 HD 发病机制尚不清楚。在这里，我们证明通过在小鼠中敲除 Ntrk2/Trkb 来破坏 iSPN 的功能，会导致纹状体多巴胺和中脑多巴胺能神经元增加，先于运动过度功能障碍。在症状前阶段对 iSPN 的转录组分析显示代谢途径失调，包括谷胱甘肽 S-转移酶 omega-2（GSTO2）编码基因 Gsto2 的上调。体内选择性降低 iSPN 中的 Gsto2 可有效预防多巴胺能功能障碍，并阻止运动过度症状的发作和进展。这项研究揭示了改变的 iSPN BDNF-TrkB 信号、谷胱甘肽-抗坏血酸代谢和高多巴胺能状态之间的功能联系，强调了 GSTO2 在维持多巴胺平衡中的重要作用。

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