When Programmed Cell Death Goes Wrong in Huntington’s Disease

This student-written blog post by Tin K. is about a neurodegenerative disease called Huntington’s Disease, and the relationship the disease progression has to programmed cell death. Take it away, Tin!

I find the programmed cell death in Huntington’s disease interesting because it shows how the same biological process that helps build the brain can also contribute to its degeneration when it is improperly regulated. It fascinates me that neurons depend on a delicate balance of death and life signals, that one single genetic mutation can disrupt this balance. This highlights how small molecular changes can have major effects on brain function, linking cellular biology directly to neurodegenerative diseases.

Imagine setting up a huge electrical network and running way more cables than you actually need. At first, everything is overbuilt on purpose. Then the system starts testing connections. The cables that successfully connect and carry signals stay. The ones that never connect or don’t work properly get removed. Your brain develops in a very similar way. Early on, it produces billions of neurons, far more than it will actually need. Each neuron has to prove itself by forming stable, functional connections with other neurons. The ones that succeed get survival signals and remain part of the network. The ones that fail are eliminated through a built-in self-destruct process called programmed cell death, or apoptosis (Chi et al., 2018). This is not a mistake. It is a normal and necessary part of development that helps fine-tune your brain into an efficient, working system.

But here’s where things go wrong in Huntington’s Disease (HD). What is supposed to be a tightly controlled developmental tool gets switched back on later in life, when it shouldn’t be (Chi et al., 2018). Instead of protecting stable, working neurons, the brain starts losing them. A genetic mutation causes neurons to activate death pathways in the striatum and cerebral cortex that are normally kept silent in adulthood (Sebastián-Serrano et al., 2025). Over time, this slowly breaks down critical brain circuits.

Figure 1. This diagram illustrates the specific molecular pathways comparison between normal neuron and Huntington’s Disease neuron with brain-derived neurotrophic factor (BDNF) gene dysregulation, leading to progressive loss of neurons (image from Speidell et al., 2023).

During development, neurons are basically competing for survival. They depend on molecules called neurotrophic factors, which act like biochemical survival signals. Neurons that form strong, useful connections receive enough of these signals to stay alive. Neurons that fail to connect properly do not get enough support and activate apoptosis (Binder & Scharfman, 2004). This process helps clean up excess neurons and ensures the brain’s wiring is precise. In adulthood, most neurons stop dividing entirely and actively suppress their death programs. This allows them to survive for decades and maintain the circuits responsible for movement, memory, and emotion.

Figure 2. This diagram illustrates the complex intracellular pathways leading to neuronal loss in Huntington’s Disease (HD) (image from Guo et al., 2024).

In Huntington’s disease, the balance starts to collapse, caused by a mutation in the huntingtin gene, which produces an abnormal version of the huntingtin protein called mHTT (Guo et al., 2024). This defective protein disrupts several essential systems inside the cell, including mitochondria, which produce energy (Guo et al., 2024). It even alters which genes get turned on or off. All of this creates stress inside the neuron and pushes it closer to activating apoptosis. Neurons that should remain stable instead begin to die. This damage is especially severe in a brain region called the striatum, which plays a major role in controlling movement and behavior (Sebastián-Serrano et al., 2025). As these neurons are lost, people with Huntington’s disease develop symptoms like uncontrolled movements, cognitive decline, and emotional changes. What makes this especially tragic is that the very same self-destruct system that helped build the brain during development is now contributing to its breakdown.

Figure 3. This diagram illustrates the pathophysiology of Huntington’s Disease, where mutant huntingtin (mHTT) proteins triggers cellular failures, leading to progressive neuronal death (image from Shah et al., 2025).

Understanding this process gives scientists important clues about how neurons survive and why they sometimes don’t. It shows that neuronal survival depends on a delicate balance between life and death signals. When that balance is disrupted, the consequences can be devastating. Researchers hope that by understanding how Huntington’s disease activates these death pathways, they can find ways to protect neurons and slow or stop the disease. Programmed cell death is not the enemy; it is a necessary tool. The real problem is when that tool gets activated at the wrong time.

Works Cited:

Binder, D. K., & Scharfman, H. E. (2004). Mini review. Growth Factors, 22(3), 123–131. https://doi.org/10.1080/08977190410001723308

Chi, H., Chang, H.-Y., Sang, T.-K., (2018). Neuronal cell death mechanisms in major neurodegenerative diseases. In International Journal of Molecular Sciences. https://doi.org/10.3390/ijms19103082

Guo, D., Liu, Z., Zhou, J., Ke, C., & Li, D. (2024). Significance of programmed cell death pathways in neurodegenerative diseases. International Journal of Molecular Sciences, 25(18), 9947. https://doi.org/10.3390/ijms25189947

Sebastián-Serrano, Á., Simón-García, A., Santos-Galindo, M., Sánchez-Carralero, M. P., H-Alcántara, A., Clemente, C., Pose-Utrilla, J., Campanero, M. R., Porlan, E., Lucas, J. J., & Iglesias, T. (2025). Down-regulation of neuroprotective protein kinase D in Huntington´s disease. Cell Death and Disease, 16(1), 418. https://doi.org/10.1038/s41419-025-07688-9

Shah, S., Mansour, H. M., & Lucke-Wold, B. (2025). Advances in Stem Cell Therapy for Huntington’s Disease: A Comprehensive Literature Review. Cells, 14(1), 42. https://doi.org/10.3390/cells14010042

Speidell, A., Bin Abid, N., & Yano, H. (2023). Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington’s Disease: Mechanisms and Potential Therapeutics. In Tatiana Ilchibaeva (Ed.), Biomedicines. https://doi.org/10.3390/biomedicines11082275