Enzyme may be key in driving Huntington’s motor symptoms
Mouse study points to GST02 levels in neurons
Higher levels of an enzyme called GST02 in the most affected neurons in Huntington’s disease could underlie early increases in the brain-signaling chemical dopamine that are believed to drive Huntington’s motor symptoms, according to a mouse study.
Scientists had previously uncovered that a deficiency in a signaling pathway called BDNF-TrkB in these neurons may lead to dopamine increases and subsequent motor dysfunction, but exactly how this might occur was unclear.
Through a series of experiments in mice lacking TrkB, a team led by researchers at University of Oxford found that this might be driven by increased levels of GST02. Suppressing the production of this enzyme before symptoms arose prevented the onset of motor problems in the mice.
“This research marks the first time that we have been able to identify a specific chemical change that is unique to the development of Huntington’s disease,” Liliana Minichiello, PhD, the study’s senior author and an Oxford professor, said in a university press release. “Understanding these early changes provides crucial insights into how Huntington’s Disease develops, and this knowledge could help develop preventive therapies to maintain dopamine balance and delay or halt disease progression.”
The study, “Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction,” was published in Nature Metabolism.
Damage done before symptoms appear
Huntington’s is caused by mutations in the HTT gene that result in production of an abnormal huntingtin protein that toxically accumulates in the brain, leading to significant motor dysfunction and other symptoms.
The mechanisms underlying exactly how Huntington’s symptoms arise are not completely understood. By the time patients start having symptoms, there’s usually already a substantial amount of brain damage.
“The big problem with Huntington’s disease is that by the time that symptoms develop much of the damage has already been done,” Minichiello said. “It is fundamental that we understand the changes that occur before the disorder develops if we are to develop effective therapeutics.”
A set of nerve cells called indirect pathway spiny projection neurons, or iSPNs, are particularly affected early on in the course of Huntington’s. This is believed to lead to excessive signaling of dopamine, a major chemical messenger in the brain, which in turns contributes to the motor symptoms that mark Huntington’s.
The mechanisms behind this dopamine dysfunction are still being explored, but previous research by Minichiello and colleagues points to a deficiency in the BDNF-Trkb signaling pathway within iSPNs.
Now, the scientists further explored the role of this pathway in driving Huntington’s symptoms.
They first showed that mice genetically engineered to lack TrkB in iSPNs developed motor dysfunction that was preceded by elevated dopamine levels in the brain, “reminiscent of the dopaminergic dysfunction observed in the brains of patients with HD [Huntington’s disease],” the researchers wrote.
Additional experiments in these mice uncovered molecular changes that might explain how a TrkB deficiency drives dopamine dysfunction. In particular, activity of the Gsto2 gene was significantly increased in iSPNs before symptom onset, after which it returned to normal levels, resembling dopamine level dynamics.
The Gsto2 gene provides instructions to produce an enzyme with the same name that’s important for preventing oxidative stress, a type of cellular damage that arises when there is an imbalance in toxic reactive oxygen molecules and the antioxidants that combat them. It’s been implicated in other neurodegenerative conditions, but hasn’t been well explored in the context of Huntington’s.
In the Trkb-deficient mice, increased Gsto2 activity, a proxy of higher GST02 levels, was associated with severe deficits in energy production within iSPNs that contributed to dopamine dysregulation and iSPNs vulnerability prior to motor symptom onset.
Higher GST02 levels were also associated with significantly lower levels of vitamin C, a broad-spectrum antioxidant with neuroprotective properties.
Rats and people
The researchers observed similarly increased Gsto gene activity in affected brain regions of a rat model of Huntington’s in the presymptomatic stages, as well as in brain tissue from people carrying Huntington’s-causing mutations but not yet showing motor symptoms.
A loss of BDNF-Trkb signaling with iSPNs could cause an increase in Gsto2 activity that ultimately drives dopamine elevations and related motor problems, according to the researchers. GST02 could thus be a target for therapeutic intervention in Huntington’s.
Suppressing the production of GST02 in Trkb-deficient mice at early stages prevented the onset of motor symptoms. It also helped normalize dopamine signaling and energy dynamics.
The researchers said the study found “a functional link between altered iSPN BDNF-TrkB signalling … metabolism and [excessive dopamine] state, underscoring the vital role of GSTO2 in maintaining dopamine balance.”
“Despite our significant understanding of its [disease mechanisms], HD remains without a cure, which underscores the necessity of delivering diagnostic and therapeutic interventions prior to the onset of symptoms, and this study is a step in that direction,” said Yaseen Malik, PhD, the study’s first author and a postdoctoral research assistant at the University of Oxford.
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