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New research published by the Minichiello group in Nature Metabolism has identified a key biochemical mechanism relevant to Huntington’s Disease, which opens the possibility of studying the disease before its clinical onset.

The illustration shows the upregulation of Gsto2, which encodes the glutathione S-transferase omega-2 (GSTO2) enzyme induced by the absence of TrkB signalling in the indirect pathway spiny projection neurons (iSPNs), the initially affected cells in Huntington’s disease, triggers an increase in dopamine, neuronal vulnerability, and motor dysfunction. The selective reduction of this protein activity in mice prevents dopamine and energy metabolism dysfunction, arresting the onset of motor symptoms.
Illustration from: Nat Metab (2024). https://doi.org/10.1038/s42255-024-01155-z
The illustration shows the upregulation of Gsto2, which encodes the glutathione S-transferase omega-2 (GSTO2) enzyme induced by the absence of TrkB signalling in the indirect pathway spiny projection neurons (iSPNs), the initially affected cells in Huntington’s disease, triggers an increase in dopamine, neuronal vulnerability, and motor dysfunction. The selective reduction of this protein activity in mice prevents dopamine and energy metabolism dysfunction, arresting the onset of motor symptoms. Illustration from: Nat Metab (2024). https://doi.org/10.1038/s42255-024-01155-z

Alterations in dopamine function have been linked to both motor and cognitive symptoms in Huntington’s disease (HD), an inherited rare neurodegenerative disorder caused by a mutation in a gene called Huntingtin (HTT). However, the cause of the dopamine surge potentially affecting neuronal health has remained elusive.

The group used cell-type-specific disruption of TrkB signalling in the indirect pathway spiny projection neurons (iSPNs), the cells most affected by HD in the early phase. They discovered that depleting the iSPNs of TrkB signalling leads to increased striatal dopamine due to an increase in the number of dopaminergic cells in the midbrain dopaminergic areas switching from a low dopamine-producing state to a high dopamine-producing state, resulting in striatal neuron vulnerability and motor dysfunction.

To identify the molecular changes that result in elevated striatal dopamine levels, the group analysed the transcriptome of the impacted neurons using RNA sequencing from our previously optimised approach. Their bioinformatic analysis revealed surprising molecular alterations happening during the presymptomatic phase.

The most surprising discovery was the upregulated expression of an enzyme in the glutathione metabolism pathway, glutathione transferase-omega2 (GSTO2).

Research by the group indicates that this enzyme activity enhances dopamine levels by regulating ascorbic acid homeostasis. Consequently, energy metabolism is affected, resulting in progressive motor dysfunction.

Using intracranial injections of a lentiviral short hairpin RNA (shRNA) construct to lower Gsto2 selectively in iSPNs of Trkb mutant mice prevented the dopaminergic dysfunction, improved energy metabolism, and other molecular rescues. Most importantly, it arrested the development of early—and late-onset motor symptoms.

To find relevance to HD, the group used striatal tissues from the SPRDtgHD rat model, which is known to show biphasic changes in dopamine, with early increases followed by later decreases. A similar upregulation in striatal levels of GSTO2 was observed during the presymptomatic phase, concomitant with BDNF downregulation before the increases in dopamine.

Intriguingly, RNA-seq analysis from very rare brain material obtained from two patients with HD at the asymptomatic phase showed similar alterations in striatal GSTO2.

These similarities with our model carrying TrKB depletion in iSPNs suggest a new concept for BDNF–TrkB signalling in the context of striatal protection modulating dopamine circuits through metabolic pathways such as glutathione–ascorbate and energy metabolism.

The paper, by joint first authors Malik YM, Guo F et al., and titled: 'Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction', is published in Nature Metabolism and can be viewed at: https://www.nature.com/articles/s42255-024-01155-z#article-info

With associated Research Briefing that can be found at:  https://rdcu.be/dYzEC

And University of Oxford press release: Discovery of key mechanism in Huntington’s Disease could pave the way

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