In the complex world of neuroscience, Huntington’s disease remains a cruel mystery. It slowly strips away a person’s ability to think and move, yet scientists still don’t fully understand why. Researchers at the University at Buffalo have spent over ten years trying to unravel that mystery. Now, they’ve uncovered two tiny but powerful proteins that may hold the key to stopping the disease before it causes irreversible damage.
What Happens in Huntington’s Disease?
Huntington’s disease is a rare but devastating condition caused by a genetic mutation in the huntingtin (HTT) gene. This mutation happens when the gene’s DNA code repeats a sequence—cytosine, adenine, guanine (CAG)—too many times. In people with Huntington’s, the number of repeats often goes beyond 36. That small change has big consequences: the altered gene creates a mutated HTT protein that leads to the death of brain cells.
Most people start to show symptoms around middle age. These can include trouble with movement, thinking, and mood. Eventually, the disease becomes fatal. For years, researchers knew that HTT helped with moving cell parts along thin structures called axons, which are like highways inside neurons. But no one could explain how the mutated version disrupted that process so badly.
Cell Traffic and Dead Ends
In 2014, the same team at UB discovered that the normal HTT protein worked like a traffic controller. It helps move important cargo along the axons using tiny transport vehicles called vesicles. These vesicles travel thanks to motor proteins like kinesins and dyneins. Without HTT, that cargo gets stuck. Traffic jams form in the neurons, and cells begin to die.
That early discovery led to a bigger question: What tells HTT when to go, stop, or change direction?
This year, the team found the answer. Two signaling proteins, GSK3β and ERK1, help regulate that whole transport system. Both proteins are types of kinases, meaning they add small phosphate tags to other proteins to change how they function. But while both are involved, they have opposite effects.
The Good and the Bad
To test their theory, scientists used fruit flies genetically altered to have the same HTT mutation as in Huntington’s disease. When they blocked GSK3β, the flies showed fewer traffic jams in their neurons. Their cells were healthier, and the flies could even crawl better. But when they blocked ERK1, the opposite happened. More blockages formed, and more neurons died.
“With these findings, we propose that ERK1 may protect neurons in the face of Huntington’s disease, while GSK3β may exacerbate it,” said Dr. Shermali Gunawardena, a senior author on the study and associate professor at UB.
When the researchers increased ERK1 levels instead of blocking it, they saw reduced damage in the cells. That suggests that treatments boosting ERK1 or lowering GSK3β could one day help slow or even stop the disease.
“There’s not much that can be done once cells have died,” Gunawardena said. “So our whole research is trying to figure out these key, early processes that lead to cell death and whether that can be prevented.”
Zooming in on the Cellular Map
To dig deeper, the team used stem cell-derived neurons from people with and without the HTT mutation. They isolated membrane structures from the cells and used advanced mass spectrometry to analyze the proteins attached to HTT. What they found shocked them: mutant HTT caused a dramatic shift in the types of proteins it interacted with.
In healthy neurons, HTT attached to proteins that support cell communication and transport. But in mutant cells, it was linked with different proteins—many of them involved in stress responses and cell death. This suggested that the mutated HTT protein wasn’t just broken. It was actively interfering with other essential cell processes.
They also saw higher levels of GSK3β and lower levels of ERK1 in the diseased neurons. Even more, the active form of GSK3β was significantly elevated, while the helpful form of AKT1, another regulator protein, was lower. That’s important because AKT1 normally keeps GSK3β in check. When AKT1 is down and GSK3β is up, it creates the perfect storm for neuron damage.
The fruit fly experiments confirmed these results. Blocking GSK3β in flies reduced both transport blockages and brain cell death. On the other hand, reducing ERK1 levels made things worse—more damage, more dysfunction. But when ERK1 was boosted, many of those problems improved.
“The level of ERK1 is clearly important for Huntington’s disease,” said Thomas J. Krzystek, the study’s first author. “Even if we don’t know exactly how it works, the pathway clearly protects neurons.”
A Path to Better Treatments
Scientists now believe that the early stages of Huntington’s disease involve a disruption of HTT’s normal role as a scaffold. In healthy cells, HTT helps bring other proteins together at membranes, like parts on a workbench. These include the motor proteins that move cargo and the membrane proteins that receive signals from the rest of the body. But when HTT is mutated, it can no longer hold these pieces in place.
As a result, entire signaling networks break down. The kinases that should be moving around the cell end up clumping together or disappearing from key areas. That makes it harder for neurons to maintain communication and health.
Among the biggest disruptions was in a group of pathways related to axon guidance, membrane trafficking, and vesicle transport. These pathways are vital for neuron survival. In the diseased cells, proteins like RAB7 and kinesin-1 showed abnormal patterns. That suggests they were either being trapped by the mutant HTT or unable to reach their proper locations.
These findings are significant because both GSK3β and ERK1 are already targets in other areas of drug development. Small molecule inhibitors for GSK3β and activators for ERK1 exist and are being explored in diseases like Alzheimer’s and cancer.
“Future treatment could potentially increase a patient’s levels of ERK1 to mitigate their neuronal cell death,” Gunawardena said. “That would need to be done carefully so it doesn’t affect other processes.”
Published in the journal, Nature Cell Death & Disease, the work was funded by the National Institute of Neurological Disorders and Stroke, as well as support from UB’s Mark Diamond Research Fund, the Stephanie Niciszewska Mucha Fund, and the BrightFocus Foundation.
Though Huntington’s disease has no cure today, the research brings new hope. By targeting key regulators like GSK3β and ERK1, scientists are getting closer to slowing or stopping the condition before damage becomes permanent. And with each new discovery, the tangled web of HTT and its deadly mutation becomes a little clearer.
