Neurodegenerative Diseases Hinge on Failure to Destroy Toxic Protein


Parkinson’s, Alzheimer’s, and Huntington’s are all diseases that devastate the brain’s neurons, leaving entire areas to become weak and die. These neurodegenerative diseases are frequently associated with the buildup of toxic proteins that lead to neuronal death.

As it turns out, it’s more complex than that. Researchers at the Gladstone Institutes have now discovered that the progression of disease is not due to the buildup of toxins itself, but rather in the individual neurons’ ability to dissolve them. Furthermore, they have established a target that could boost this ability, thus protecting the brain from the diseases’ deadly effects.

Optical Pulse Labeling

Scientists describe in the latest issue of Nature Chemical Biology how a newly developed technology allowed them for the first time to see how individual neurons fight back against the buildup of toxic proteins over time.

Focusing their efforts on a model of Huntington’s disease, the team observed how different types of neurons in the brain each responded to this toxic buildup with different degrees of success, offering clues as to why the disease causes neurons in one region to die, while neurons in another are spared.

“Huntington’s—an inherited and fatal disorder that leads to problems with muscle coordination, cognition and personality—is characterized by the toxic buildup of a mutant form of the huntingtin protein in the brain,”

explained Dr. Steve Finkbeiner, director of the Taube-Koret Center for Neurodegenerative Disease Research at Gladstone.

“A long-standing mystery among researchers was how the buildup of this mutant huntingtin caused cells to degrade and die, but previous technology made it virtually impossible to monitor this process at the cellular level. In this study, we employed a method called optical pulse-labeling, or OPL, which allowed us to see how the mutant huntingtin ravaged the brain over time—neuron by neuron.”

The Optical Pulse Labeling method used by the research team tracked the speed and efficiency with which different types of neurons were able to break down and dissolve the mutant huntingtin. The faster a cell cleared out the toxins, the longer the neuron survived.

Researchers noticed obvious differences in the ability of different types of neurons to clear mutant huntingtin. Neurons located in the striatum, the region of the brain involved in movement that is primarily affected by Huntington’s, were particularly vulnerable.

Neurons found in other regions, such as the cortex and cerebellum, were less so. When the striatal neurons carrying the mutant huntingtin were tracked over time, they found them much more likely to die than those from other brain regions.

The Brain’s Powerful Coping Mechanisms

“If we could develop drugs that boost Nrf2 production in the neurons most susceptible to Huntington’s, we might extend their survival, thereby staving off the worst effects of the disease,”

said Andrey Tsvetkov, PhD, the study’s lead author.

“Importantly, our results also demonstrate that the brain itself has evolved powerful coping mechanisms against diseases such as Huntington’s. For example, the fact that people don’t start experiencing symptoms of Huntington’s until the fourth or fifth decade of their lives—even though the mutant huntingtin is present at birth—is further evidence of the brain’s ability to stave off the effects of the disease.”

“Our findings are critical not only to inform us as to the underlying mechanisms behind diseases such as Huntington’s, but also to remind researchers that focusing on the disease-causing protein—and not how individual cells respond to it–is only one side of the coin. To truly understand a complex disease like Huntington’s, we must also look to the brain’s naturally evolved defense mechanisms, which as we’ve shown here could represent an entirely new therapeutic strategy,”

said Dr. Finkbeiner.


Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration
Andrey S Tsvetkov, Montserrat Arrasate, Sami Barmada, D Michael Ando, Punita Sharma, Benjamin A Shaby & Steven Finkbeiner
Nature Chemical Biology (2013) doi:10.1038/nchembio.1308

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Last Updated on December 16, 2022