Key Proteins Play Opposing Roles in Huntington's Disease Progression

Recent research from the University at Buffalo has shed new light on the molecular mechanisms underlying Huntington's disease, a devastating neurodegenerative disorder. A decade ago, scientists discovered that the mutated huntingtin protein (HTT) functions as a traffic controller within neurons, facilitating the transport of vital cellular cargo along axons through interactions with other proteins. Disruptions in this transport system are central to the neuronal damage seen in Huntington's disease.

Advancing this understanding, researchers have identified two specific signaling proteins, GSK3β and ERK1, which influence HTT’s role in neuronal transport. Their findings reveal that GSK3β is upregulated in neurons affected by Huntington's disease. When this protein's activity was inhibited in fruit fly models expressing mutant HTT, there was a significant reduction in axonal transport disruptions and neuronal cell death, leading to improved motor functions in the flies. Conversely, inhibiting ERK1 resulted in increased transport deficits and neural degeneration, suggesting that ERK1 may have a protective role.

Dr. Shermali Gunawardena, a lead researcher, emphasized that these discoveries suggest potential therapeutic avenues: targeting GSK3β for inhibition while boosting ERK1 activity could help mitigate neuronal damage. While the precise mechanisms are still being explored, these findings open promising pathways for developing treatments aimed at early intervention in Huntington's disease.

The team focused on kinases like GSK3β and ERK1 because they modify HTT and other transport components through phosphorylation, affecting their function. Elevated levels of GSK3β appear to worsen the disease process, whereas ERK1 seems to confer neuroprotection. These insights underscore the importance of kinase regulation in neuronal health and disease and suggest that manipulating these proteins might slow or prevent the progression of Huntington's disease.

Published in "Cell Death & Disease," this research highlights the complexity of intracellular transport regulation and offers hope for targeted therapies that can alter disease trajectory, potentially improving quality of life for patients.

Source: https://medicalxpress.com/news/2025-05-protein-mitigates-huntington-disease-exacerbates.html