In the intricate realm of neuroscience, Huntington’s disease continues to perplex scientists with its devastating effects on cognitive and motor functions. Despite decades of research, the exact mechanisms behind this neurodegenerative disorder remain elusive. However, a team of researchers at the University at Buffalo has made a significant breakthrough. After more than ten years of dedicated study, they have identified two small but potent proteins that could potentially halt the progression of the disease before it inflicts irreversible damage.
Huntington’s disease is a rare genetic disorder caused by a mutation in the huntingtin (HTT) gene. This mutation results from an excessive repetition of the DNA sequence cytosine, adenine, guanine (CAG) within the gene. When the number of repeats exceeds 36, it leads to the production of a mutated HTT protein, which ultimately causes the death of brain cells. Symptoms typically manifest in middle age and include difficulties with movement, cognition, and mood, eventually proving fatal.
Understanding the Cellular Traffic Jam
In 2014, the University at Buffalo team discovered that the normal HTT protein functions as a traffic controller within neurons. It facilitates the movement of essential cellular components along axons, the thin structures that serve as highways within neurons. This transport is carried out by tiny vesicles powered by motor proteins such as kinesins and dyneins. Without the proper function of HTT, these cellular components become stuck, resulting in traffic jams that lead to cell death.
The recent discovery sheds light on the regulatory mechanism of this transport system. Two signaling proteins, GSK3β and ERK1, have been identified as key players. Both are kinases, enzymes that modify other proteins by adding phosphate groups, thereby altering their function. Interestingly, these proteins have opposing effects on the transport system.
The Role of GSK3β and ERK1
To test their hypothesis, the researchers conducted experiments using fruit flies genetically modified to carry the same HTT mutation found in Huntington’s disease. Blocking GSK3β in these flies resulted in fewer neuronal traffic jams, healthier cells, and improved motor functions. Conversely, inhibiting ERK1 led to increased blockages and neuron death.
“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 of the study and associate professor at UB.
Further experiments showed that increasing ERK1 levels reduced cellular damage, suggesting that therapies aimed at boosting ERK1 or reducing GSK3β could potentially slow or halt the disease’s progression.
Zooming in on the Cellular Map
To delve deeper, the research team utilized stem cell-derived neurons from individuals with and without the HTT mutation. By isolating membrane structures and employing advanced mass spectrometry, they analyzed the proteins interacting with HTT. The results were surprising: mutant HTT was associated with proteins involved in stress responses and cell death, rather than those supporting cell communication and transport.
This shift indicates that the mutated HTT protein actively disrupts essential cellular processes. The researchers also observed elevated levels of active GSK3β and reduced levels of ERK1 in diseased neurons. The active form of GSK3β was significantly increased, while AKT1, another regulatory protein that typically keeps GSK3β in check, was diminished. This imbalance creates a detrimental environment for neuronal health.
Implications for Future Treatments
The study’s findings suggest that the early stages of Huntington’s disease involve a disruption of HTT’s role as a scaffold for other proteins. In healthy cells, HTT assembles proteins at membranes to facilitate cellular communication and transport. However, the mutated HTT fails to maintain these connections, leading to the breakdown of signaling networks crucial for neuron survival.
Among the most affected pathways are those related to axon guidance, membrane trafficking, and vesicle transport. Proteins like RAB7 and kinesin-1 exhibited abnormal patterns in diseased cells, indicating their entrapment by mutant HTT or inability to reach their destinations.
GSK3 inhibition mitigates larval locomotion defects, axonal transport blockages, abnormal synaptic morphology, and elevated neuronal cell death elicited by pathogenic HTT. (CREDIT: Nature Cell Death & Disease)
These insights are promising because both GSK3β and ERK1 are already targets in drug development for other conditions, such as Alzheimer’s and cancer. Small molecule inhibitors for GSK3β and activators for ERK1 are under exploration, offering potential therapeutic avenues for Huntington’s disease.
“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.”
A New Hope for Huntington’s Disease
Published in the journal, Nature Cell Death & Disease, this groundbreaking research was funded by the National Institute of Neurological Disorders and Stroke, with additional support from UB’s Mark Diamond Research Fund, the Stephanie Niciszewska Mucha Fund, and the BrightFocus Foundation.
Although Huntington’s disease currently has no cure, the discovery of these regulatory proteins offers new hope. By targeting GSK3β and ERK1, scientists are moving closer to developing treatments that could slow or prevent the disease before it causes irreversible damage. With each new discovery, the complex web of HTT and its lethal mutation becomes a little clearer, paving the way for future breakthroughs.
