Summary: Researchers have identified a key biochemical mechanism that may allow Huntington’s disease to be detected and studied before symptoms appear, offering new opportunities for early intervention. The team discovered that disrupted dopamine regulation in a specific population of neurons, linked to impaired TrkB neurotrophin receptor signaling, appears to trigger disease onset. By targeting an enzyme called GSTO2, researchers prevented motor symptoms in a mouse model, suggesting this protein plays a role in disease progression.
This finding opens avenues for developing early diagnostic tests and preventive treatments aimed at restoring dopamine balance. Addressing these early biochemical changes could delay or halt Huntington’s disease before irreversible brain damage occurs.
Key facts
- Disrupted TrkB signaling in indirect pathway spiny projection neurons (iSPNs) leads to a dopamine imbalance associated with Huntington’s symptoms.
- The enzyme GSTO2 (glutathione S-transferase omega-2) influences dopamine regulation; reducing its activity delayed motor symptoms in mice.
- Early intervention that targets this biochemical pathway may prevent or slow disease progression before clinical onset.
Source: Oxford University
Researchers at the University of Oxford have pinpointed a biochemical change connected to the development of Huntington’s disease, offering a path to study and potentially prevent the disorder before symptoms arise.
Published in Nature Metabolism, the study identifies for the first time a specific biochemical alteration that contributes to Huntington’s disease and demonstrates how blocking that change can stop disease progression in experimental models.
Huntington’s disease is an inherited neurodegenerative disorder that progressively impairs brain regions responsible for movement, cognition and behavior. Symptoms typically appear in mid-adulthood and steadily worsen, ultimately causing severe disability and death. Identifying the earliest molecular events that trigger the disease is essential for developing therapies that can prevent or delay symptom onset.
The Oxford team revisited an early observation from the 1980s suggesting a biochemical change in brains of people who later developed Huntington’s disease, and set out to determine how that change contributes to disease onset.
Their experiments focused on indirect pathway spiny projection neurons (iSPNs), the cells most vulnerable in Huntington’s. They found that when TrkB neurotrophin receptor signaling in iSPNs is disrupted, dopamine levels in the striatum rise, producing a hyperdopaminergic state that precedes motor dysfunction.
In mouse models with impaired TrkB signaling in iSPNs, increased striatal dopamine and enhanced activity of midbrain dopaminergic neurons were observed before any clear hyperkinetic behaviors. This timing suggests the dopamine imbalance is an early, driving event rather than a late consequence of neuronal degeneration.
Transcriptomic profiling of iSPNs at a pre-symptomatic stage revealed altered metabolic pathways, including a marked increase in expression of the gene Gsto2, which encodes glutathione S-transferase omega-2 (GSTO2). GSTO2 is involved in glutathione-related metabolism, a system critical for cellular redox balance and neuronal health.
To test GSTO2’s role, researchers selectively reduced its activity in iSPNs in living mice. This intervention prevented the dopaminergic and cellular energy metabolism disturbances and stopped the emergence and progression of hyperkinetic motor symptoms. The protective effect supports a causal role for GSTO2 dysregulation in driving early dopamine imbalance and motor dysfunction.
Crucially, similar GSTO2 dysregulation was detected in a rat model of Huntington’s disease and in rare brain samples from individuals who carried the disease-causing mutation but had not yet developed symptoms, reinforcing the enzyme’s potential importance in human disease.
Professor Liliana Minichiello, lead author and Professor of Cellular and Molecular Neuroscience at Oxford’s Department of Pharmacology, emphasized the challenge Huntington’s disease poses because much damage is already established by the time symptoms manifest. She noted that identifying biochemical changes that occur before symptom onset is essential to design effective therapeutics and early diagnostic tests.
Dr Yaseen Malik, first author of the paper, added that although the biological mechanisms of Huntington’s are increasingly well understood, the condition currently has no cure. This study takes a step toward diagnostic and therapeutic strategies that could be applied before symptoms arise.
About this Huntington’s disease research news
Author: Caroline Wood
Source: Oxford University
Contact: Caroline Wood – Oxford University
Image: Image credited to Neuroscience News
Original Research: Open access. “Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction” by Liliana Minichiello et al. Nature Metabolism
Abstract
Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction
Identifying the initial triggering events in neurodegenerative disorders is critical for developing preventive therapies. In Huntington’s disease (HD), a hyperdopaminergic state—likely triggered by dysfunction of indirect pathway spiny projection neurons (iSPNs)—is thought to produce hyperkinesia, an early symptom of HD. How this change arises and contributes to disease pathogenesis, however, was not clear.
This study demonstrates that genetic disruption of iSPN function through Ntrk2/TrkB deletion in mice leads to increased striatal dopamine and elevated midbrain dopaminergic neuron activity, preceding hyperkinetic dysfunction. Transcriptomic analysis at a pre-symptomatic stage revealed deregulation of metabolic pathways, including upregulation of Gsto2. Selectively reducing Gsto2 in iSPNs in vivo prevented dopaminergic dysfunction and halted the onset and progression of hyperkinetic symptoms. These results reveal a functional link between altered iSPN BDNF–TrkB signaling, glutathione–ascorbate metabolism and a hyperdopaminergic state, highlighting the critical role of GSTO2 in maintaining dopamine balance.