Spring Cleaning Damaged Proteins with Nrf2: Good for Huntington’s Disease and Other Neurodegenerative Disorders?
The study published in Nature Chemical Biology explains how important it is to quickly clear damaged proteins from neurons. Cell survival may be affected by the speed at which damaged proteins are removed. In Huntington’s disease and other neurodegenerative disorders, damaged proteins become misshaped and abnormal.
Neuro Nrf2

A new study supported by grants from NINDS and the National Institute on Aging as well as funding provided by the Taube/Koret Center, the National Science Foundation , the Huntington’s Disease Society of America, the Milton Wexler Award, and the Hillblom Foundation shows that activating a gene known as NRF2 helps clear damaged proteins which slows down or could possibly prevent Huntington’s disease.

The study published in Nature Chemical Biology explains how important it is to quickly clear damaged proteins from neurons. Cell survival may be affected by the speed at which damaged proteins are removed. In Huntington’s disease and other neurodegenerative disorders, damaged proteins become misshaped and abnormal. They envelope neurons and damage or kill the nearby brain cells. Healthy bodies are able to control quality and quantity of protein levels, as well as is able to detect malformed proteins and flush them be fore they can do any damage through a process called proteostasis.

The study broke new ground in developing and using a technique called optical pulse-labeling to measure how quickly damaged proteins get removed. “Before this new technique, there was no way to look at individual neurons and their capacity to handle proteins. This method provides a real-time readout of how fast proteins are turned over in neurons and gives us a look at some of the mechanisms involved,” said Margaret Sutherland, Ph.D., program director at NINDS.

The research studied the impact of different forms of huntingtin, the protein in Huntington’s disease on neuron death and the symptoms of the disease. The experiments showed that the mutant form of huntingtin caused more rat cells to die than the normal healthy form of the protein.

To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer. The researchers discovered that neuronal survival is directly correlated with the amount of time a neuron is exposed to the mutant huntingtin protein. Improving proteostasis in Huntington’s brains may improve neuronal survival and slow down or even prevent the the progression of the disease.

“Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin,” said Dr. Steven Finkbeiner, senior author of the paper.

“These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don’t cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good,” said Dr. Finkbeiner.

Other NRF2 Huntington studies on Pubmed.org:

Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin.


Extremely low-frequency electromagnetic fields activate the antioxidant pathway Nrf2in a Huntington‘s disease-like rat model.


Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington‘s disease.


Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway.


Impairment of PGC-1alpha expression, neuropathology and hepatic steatosis in a transgenic mouse model of Huntington‘s disease following chronic energy deprivation.


The Nrf2 pathway as a potential therapeutic target for Huntington disease A commentary on “Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington disease”.


Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington‘s disease.


Mutant huntingtin activates Nrf2-responsive genes and impairs dopamine synthesis in a PC12 model of Huntington‘s disease.


Role of Nrf2-dependent ARE-driven antioxidant pathway in neuroprotection.


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