Researchers at the University at Buffalo have uncovered two proteins with opposing roles in Huntington’s disease: one exacerbates the condition, while the other may protect neurons. Published in Nature Cell Death & Disease on April 22, the study reveals that inhibiting glycogen synthase kinase-3beta (GSK3ß) reduces neuronal damage, whereas blocking extracellular signal-related kinase (ERK1) worsens symptoms. These findings could pave the way for targeted therapies to slow or prevent the progression of this fatal neurological disorder.
Huntington’s disease is caused by a mutation in the huntingtin protein (HTT), which disrupts cellular transport in neurons, leading to traffic jams and eventual cell death. The research team, led by Dr. Shermali Gunawardena, discovered that GSK3ß and ERK1, kinases upregulated in Huntington’s patients, play critical but opposing roles.
In experiments with fruit fly larvae, inhibiting GSK3ß reduced axonal blockages and cell death, improving mobility. Conversely, blocking ERK1 increased transport defects and accelerated neuronal damage. Elevating ERK1 levels, however, showed protective effects.
“GSK3ß appears to worsen the disease, while ERK1 acts as a safeguard,” explained Dr. Gunawardena. First author Thomas Krzystek added, “Targeting these kinases could offer new treatment avenues, suppressing GSK3ß and boosting ERK1.”
The study highlights the potential for future therapies to modulate these proteins, offering hope for delaying or mitigating Huntington’s devastating effects. Further research will explore how to safely manipulate these pathways in humans.
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