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

Mohd Yaseen Malik, Fei Guo, Aman Asif-Malik, Vasileios Eftychidis, Nikolas Barkas, Elena Eliseever, Kerstin N. Timm, Aleksandra Wolska, David Bergin, Barbara Zonta, Veronika Ratz-Wirsching, Stephan von Hörsten, Mark E. Walton, Peter J. Magill, Claus Nerlov, Liliana Minichiello

Research output: Contribution to JournalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)2100-2117
Number of pages18
JournalNature Metabolism
Volume6
DOIs
Publication statusPublished - 28 Oct 2024

Keywords

  • Animals
  • Brain-Derived Neurotrophic Factor/metabolism
  • Corpus Striatum/metabolism
  • Dopamine/metabolism
  • Dopaminergic Neurons/metabolism
  • Glutathione Transferase/metabolism
  • Glutathione/metabolism
  • Mice
  • Receptor, trkB/metabolism

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