Huntington’s disease, a debilitating genetic disorder, may finally have a pathway to remedies thanks to groundbreaking research recognizing its biochemical trigger. This discovery paves the way for early interventions and therapies promising to halt or even reverse the disease’s progression.
Published in Nature Metabolism, the study identifies a specific biochemical change occurring within the brain that initiates Huntington’s disease. This finding alone is monumental, marking the first time scientists have pinpointed a chemical change uniquely associated with the disease’s development.
Early Onset: Understanding the Cause Before Symptoms Emerge
Huntington’s disease, characterized by a progressive decline in brain function leading to both mental and physical deterioration, typically manifests after the age of 30. Symptoms worsen over a decade or two, ultimately becoming fatal. The new research, however, suggests that these detrimental changes begin much earlier, in a specific type of neuron called indirect pathway spiny projection neurons (iSPNs).
These neurons are among the first affected by Huntington’s. Dysfunction within these iSPNs disrupts dopamine balance in the brain. This disruption stems from a faulty neurotrophin receptor, TrkB, which fails to function properly, triggering early disease symptoms, including involuntary movements.
Targeting the Dopamine Connection
The research team observed that mice lacking normal function in these iSPNs due to disrupted TrkB signaling exhibited elevated dopamine levels, resulting in hyperactivity. This alteration occured before any noticeable symptoms appeared, highlighting the critical role of dopamine balance in the early stages of Huntington’s disease.
Furthermore, the study identified a protein called GSTO2 as a key player in regulating dopamine levels. By selectively reducing GSTO2 activity in mice, researchers were able to prevent dopamine and energy metabolism dysfunction, effectively halting the onset of motor symptoms.
Notably, GSTO2 dysregulation was observed in a rat model of Huntington’s and in the brains of some asymptomatic HD patients, underscoring its potential relevance to the disease’s development.
A New Era of Treatment and Diagnosis
“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,” stated Professor Liliana Minichiello, lead author of the study.
This discovery provides a critical window of opportunity for early intervention. The identification of this unique biochemical change opens doors for developing new diagnostic tests to detect early signs 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,” added Professor Minichiello.
“Despite our significant understanding of its pathophysiology, 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,” Dr. Yaseen Malik, first author of the paper, concluded.
Reference: “Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction” 28 October 2024, Nature Metabolism.
DOI: 10.1038/s42255-024-01155-z