Journal article
Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 14.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s42255-024-01155-z
Authors
+ University of Oxford
More from this funder
- Funder identifier:
- https://ror.org/052gg0110
- Funding agency for:
- Minichiello, L
- Grant:
- ISSF-2019
- Programme:
- Institutional Strategic Support Fund
+ British Heart Foundation
More from this funder
- Funder identifier:
- https://ror.org/02wdwnk04
- Funding agency for:
- Timm, KN
- Grant:
- RE/18/3/34214
+ Medical Research Council
More from this funder
- Funder identifier:
- https://ror.org/03x94j517
- Funding agency for:
- Minichiello, L
- Bergin, D
- Magill, PJ
- Nerlov, C
- Grant:
- MR/W005166/1
- MC_UU_00003/5
- MC_UU_12009/7
+ China Scholarship Council
More from this funder
- Funder identifier:
- https://ror.org/04atp4p48
- Funding agency for:
- Guo, F
- Grant:
- 201608060286
+ Commonwealth Scholarship Commission
More from this funder
- Funder identifier:
- https://ror.org/051x4wh35
- Funding agency for:
- Malik, MY
- Grant:
- INCS-2019-225
- Publisher:
- Springer Nature
- Journal:
- Nature Metabolism More from this journal
- Volume:
- 6
- Issue:
- 11
- Pages:
- 2100-2117
- Publication date:
- 2024-10-28
- Acceptance date:
- 2024-09-30
- DOI:
- EISSN:
-
2522-5812
- ISSN:
-
2522-5812
- Language:
-
English
- Pubs id:
-
2054086
- Local pid:
-
pubs:2054086
- Deposit date:
-
2024-11-01
Terms of use
- Copyright holder:
- Malik et al.
- Copyright date:
- 2024
- Rights statement:
- © The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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