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A key biochemical change involved in the development of Huntington’s disease has been discovered by researchers from Germany and the U.K., which could provide routes for early detection and treatment.

The study published in the journal Nature Metabolism, identified reasons behind a dopamine imbalance in the neurodegenerative disorder.

This could crucially help with delivery of diagnostic and therapeutic interventions, before the first symptoms occur.

“The big problem with Huntington’s disease is that by the time that symptoms develop much of the damage has already been done, and therefore, it is fundamental that we understand the changes that occur before the disorder develops if we are to develop effective therapeutics,” explained lead author Liliana Minichiello, PhD, a professor of cellular and molecular neuroscience at the University of Oxford.

“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, which opens the possibility of developing new tests to study the early changes of the disease before irreversible damage occurs.”

Huntington’s disease is an inherited condition in which symptoms usually start around the age of 30–50 years. It usually becomes fatal within two decades of this.

The disease is characterized by memory lapses, depression, movement issues and mood swings. An imbalance in dopamine levels has been implicated in abnormal involuntary movements that are early symptoms of Huntington’s disease.

The research findings point to a specific issue with indirect pathway spiny projection neurons (iSPNs) in the brain, which are nerve cells initially affected by the inherited disease.

This affects dopamine levels, due to missed signaling derived from the activation of the neurotrophin receptor TrkB.

The researchers found that mice for which normal iSPN function had been affected due to disrupted TrkB neurotrophin signaling had increased levels of dopamine in the brain, which led to hyperactivity.

Importantly, this occurred before noticeable symptoms appeared, indicating that these changes might contribute to the early symptoms of Huntington’s disease.

The research also shines a light onto the role of an enzyme that is part of the glutathione metabolism called GSTO2.

This is important in the regulation of dopamine levels and selectively reducing the activity of this protein in mice prevented dysfunction in dopamine and energy metabolism dysfunction and arrested the onset of motor symptoms.

The enzyme demonstrated similar dysregulation in a rat model of Huntington’s disease as well as the brains of asymptomatic patients with the condition, indicating its early role in the disorder.

Collectively, the study demonstrates that Ntrk2/Trkb-mediated neurotrophic signaling regulates dopamine levels by controlling glutathione–ascorbate metabolism, thereby affecting striatal dopaminergic circuits and motor function.

Minichiello said: “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.”

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