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

Area of Science:

• Neuroscience
• Genetics
• Metabolic pathways

Background:

• Identifying early triggers for neurodegenerative disorders like Huntington's disease (HD) is crucial for developing preventive therapies.
• Hyperdopaminergia and hyperkinesia are early HD symptoms, potentially linked to dysfunction in indirect pathway spiny projection neurons (iSPNs).
• The precise mechanisms driving iSPN dysfunction and its contribution to HD pathogenesis remain unclear.

Purpose of the Study:

• To investigate the role of iSPN dysfunction in HD pathogenesis.
• To identify molecular pathways involved in early HD development.
• To explore potential therapeutic targets for preventing HD progression.

Main Methods:

• Genetic disruption of Ntrk2/TrkB in mouse iSPNs.
• Transcriptomic analysis of iSPNs at the pre-symptomatic stage.
• In vivo selective reduction of Gsto2 in iSPNs.

Main Results:

• Ntrk2/TrkB deletion in iSPNs led to increased striatal dopamine and midbrain dopaminergic neurons before hyperkinetic symptoms.
• Transcriptomic analysis revealed dysregulated metabolic pathways, including upregulated Gsto2.
• Selective Gsto2 reduction in iSPNs prevented dopaminergic dysfunction and hyperkinetic symptoms.

Conclusions:

• Altered iSPN BDNF-TrkB signaling, glutathione-ascorbate metabolism, and hyperdopaminergic state are functionally linked in HD.
• GSTO2 plays a vital role in maintaining dopamine balance.
• Targeting GSTO2 in iSPNs may offer a preventive strategy for HD.