Researchers have uncovered a critical biochemical process connected to the emergence of Huntington’s Disease. This breakthrough may allow for the examination of the disease prior to its clinical manifestation, potentially leading to methods to halt its progression.
Researchers from the University of Oxford have uncovered a crucial biochemical process associated with the onset of Huntington’s Disease. This breakthrough may pave the way for exploring the disease before it becomes clinically apparent and ultimately stopping its advancement.
Published in Nature Metabolism, the study reveals for the first time the biochemical alteration that triggers Huntington’s disease and how preventing this change can halt the disease’s progress.
Huntington’s disease is a hereditary condition that disrupts certain brain functions, resulting in a gradual decline in mental and physical abilities. Symptoms typically begin after the age of 30 and can be fatal, with some affected individuals experiencing a decline over a span of up to 20 years.
The research investigates an early change observed in the brains of Huntington’s disease patients as far back as the early 1980s that may lead to the disease’s onset. The scientists discovered that specific brain cells called indirect pathway spiny projection neurons (iSPNs), which are among the first to be impacted in Huntington’s disease, may create a dopamine imbalance due to a lack of crucial signaling from the activation of the neurotrophin receptor TrkB. This imbalance has been linked to early symptoms such as involuntary and abnormal movements.
Initially, the researchers studied mice that had impaired iSPN functions stemming from disrupted TrkB neurotrophin signaling. They observed these mice exhibited elevated dopamine levels in the brain, resulting in hyperactivity. Notably, this change occurred prior to the onset of observable symptoms, indicating that these early alterations could play a significant role in Huntington’s disease progression.
Additionally, the researchers discovered a protein named GSTO2, an enzyme involved in glutathione metabolism, is vital in regulating dopamine levels. By selectively diminishing the activity of this protein in mice, they managed to prevent issues related to dopamine and energy metabolism, successfully delaying the onset of motor symptoms.
Crucially, this enzyme displayed similar dysregulation in a rat model of Huntington’s disease and in some rare brains of asymptomatic Huntington’s disease patients, solidifying its potential importance in the disorder’s development.
The lead author of the study, Liliana Minichiello, a Professor of Cellular and Molecular Neuroscience at Oxford’s Department of Pharmacology, stated: ‘The significant challenge with Huntington’s disease is that by the time symptoms arise, much of the damage is already done. Therefore, understanding the changes that occur before the onset of the disorder is essential to developing effective treatments.’
‘This research is the first instance where we have identified a specific chemical change unique to Huntington’s disease development, which opens the door for creating new tests to investigate the early changes before irreversible harm occurs.’
‘Gaining insight into these early changes is vital for understanding how Huntington’s Disease evolves, and this information could assist in developing preventive treatments that maintain dopamine levels and potentially delay or stop the progression of the disease.’
Dr. Yaseen Malik (Department of Pharmacology, Oxford University), the first author of the paper, remarked: ‘Despite substantial knowledge of its pathophysiology, Huntington’s disease still has no cure, highlighting the urgent need for diagnostic and therapeutic measures before symptoms manifest. This study marks a meaningful step in that direction.’
