Healthcare (Commonwealth Union) – Huntington’s Disease is a hereditary neurological disorder caused by a mutation in the HTT gene, which is responsible for producing a protein called huntingtin. The defective gene leads to the production of an abnormal form of this protein, which accumulates in brain cells and causes gradual deterioration, especially in regions critical for movement, behavior, and cognition. This process eventually leads to death, generally 15-20 years after symptoms first appear.
The disease is autosomal dominant, meaning a person needs only one defective copy of the gene (inherited from either parent) to develop the disorder. If a parent has the gene, each child has a 50% chance of inheriting it.
Scientists at the University of Oxford have uncovered a crucial biochemical process linked to the onset of Huntington’s Disease. This breakthrough offers potential for researching the disease before symptoms appear and ultimately halting its advancement.
Published in Nature Metabolism, the study reveals, for the first time, the specific biochemical alteration that contributes to Huntington’s disease and demonstrates that blocking this change can prevent disease progression.
Huntington’s disease is a genetic disorder that gradually damages certain areas of the brain, resulting in progressive mental and physical decline. Symptoms typically emerge after age 30 and are ultimately fatal, though the decline may span up to 20 years.
The study delves into a brain alteration in Huntington’s patients first observed in the 1980s, which may contribute to the onset of the disease. Researchers identified that disruptions in a particular type of brain cell, called indirect pathway spiny projection neurons (iSPNs), the first cells affected in Huntington’s, could cause a dopamine imbalance due to reduced signaling from the neurotrophin receptor TrkB. This imbalance is associated with early symptoms like uncontrolled, involuntary movements.
The scientists began by studying mice lacking typical function in iSPNs due to impaired TrkB signaling. These mice showed elevated dopamine levels in the brain, leading to hyperactivity—occurring even before visible symptoms, hinting that these early shifts may play a significant role in disease development.
They also discovered that an enzyme named GSTO2, involved in glutathione metabolism, is crucial for regulating dopamine. By selectively reducing this enzyme’s activity in mice, the researchers successfully made a halt to dopamine and energy metabolism issues, stopping the development of motor symptoms in the mice.
Notably, this enzyme exhibits similar irregularities in a rat model of Huntington’s Disease and in a few rare cases of symptom-free HD patients, further supporting its potential role in the disorder’s development.
The study’s lead researcher, Professor Liliana Minichiello of Oxford’s Department of Pharmacology, indicated that a major challenge with Huntington’s disease is that by the time symptoms emerge, significant damage has already occurred. Thus, it is essential to understand the changes that happen before symptoms appear if we are to create effective treatments.
‘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.
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.’
Dr. Yaseen Malik, the paper’s lead author, remarked, although we have a substantial grasp of Huntington’s disease pathophysiology, there is still no cure. This highlights the critical need for diagnostic and therapeutic strategies to be implemented before symptoms arise, and this research represents progress toward that goal.
The paper, titled “Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction,” is available in Nature Metabolism.
