Mechanism may protect against neurodegenerative disease

By Robin Arnette

NIEHS scientists have uncovered a mechanism that may reduce the development of neurodegenerative disorders. It involves the protein NRF2 and a genetic switch that controls a brain molecule known as tau. The finding, which appeared online April 14 in Cell Reports, suggests compounds that activate the NRF2 pathway may provide some protection against the formation of brain tangles. Such compounds are often found in cruciferous vegetables, such as cauliflower, cabbage, and broccoli.
Douglas Bell, Ph.D., NIEHS senior scientist and corresponding author of the study, said that tau maintains the structure of neurons, and it exists in at least six different forms. Other researchers have determined that some forms of tau tend to stick together, producing the neurofibrillary tangles found in the brains of people with Alzheimer’s disease, Parkinson’s-like illnesses, such as progressive supranuclear palsy and corticobasal degeneration, and sometimes Parkinson’s disease. Other forms of tau are less likely to form tangles.

The genetics of disease risk

The study found that NRF2 binds to an inherited version of the tau gene, called the T allele, and this binding appears to trigger production of one of the protective, or less sticky, forms of tau. Bell pointed out that everyone has the sticky form of tau. However, people born with the T allele may be more responsive to the benefits of cruciferous vegetables.
"Genetics only explains a small percentage of the disease risk, but people with the T allele are less likely to get these neurodegenerative diseases," Bell said.

Help from bioinformatics

The research team found the link between NRF2 and the T allele of tau by integrating its genome-wide maps of NRF2 binding, genome-wide association studies of neurodegenerative disease, and other projects of the National Institutes of Health, including the Encyclopedia of DNA Elements, 1000 Genomes, GTEx, and the Roadmap Epigenomics Project.
Xuting Wang, Ph.D., a staff scientist in Bell’s group, led the bioinformatics, or data analysis, portion of the work. He believed the research would not have been possible without this big data.
"The bioinformatics tools we developed have allowed us to explain the link between NRF2 and neurodegenerative disease, and may be useful for discovery of other disease mechanisms," Wang said.
Honglei Chen, M.D., Ph.D., is a senior researcher at NIEHS who studies Parkinson’s disease. He was not involved in the study, but thinks the results will help other scientists search for modifiable risk factors for these debilitating conditions.
"This is an exciting finding that epidemiologists can follow up on, for example, by examining the potential interactions between eating cruciferous vegetables and NRF2, and their impacts on neurodegenerative diseases," Chen said.
Citation: Wang X, Campbell MR, Lacher SE, Cho H-Y, Wan M, Crowl CL, Chorley BN, Bond GL, Kleeberger SR, Slattery M, Bell DA. 2016. 2016. A polymorphic antioxidant response element links NRF2/sMAF binding to enhanced MAPT expression and reduced risk of Parkinsonian disorders. Cell Rep 15(4):830–842.

The graphic illustrates the differences between a healthy neuron, top, and a diseased neuron, bottom. In a healthy neuron, tau stabilizes the microtubules, which are part of the cell’s skeleton. In a diseased neuron, the microtubules disintegrate, forcing tau to separate from the microtubules and accumulate phosphate groups. These hyperphosphorylated tau fragments clump together and form tangles. The new study found that NRF2 is involved in controlling tau. (Photo courtesy of the National Institute on Aging)

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martes, 3 de mayo de 2016