USC researchers have found that a gene able to protect against oxidative stress – an important cell process involved in aging, inflammation and disease – may also play a role in the onset of Alzheimer’s disease.
The findings, which offer substantial leads in the quest to understand many diseases, recently appeared in the Federation of American Societies for Experimental Biology Journal, following initial observations published in the Journal of Biological Chemistry last year.
“We found that the DSCR1(Adapt78) gene protected cells from oxidative stress when expressed naturally, or in a cell line that we constructed,” said Kelvin Davies, associate dean for research at USC’s Ethel Percy Andrus Gerontology Center and principal investigator on the project. “But we also observed that this same gene can be harmful when expressed for longer periods of time.”
Davies and his colleagues found that over-expression of the DSCR1(Adapt78) gene might result in the formation of “neurofibrillary tangles” – an accumulation of a protein called tau – in the brain, which is associated with Alzheimer’s disease.
Tau proteins are regulated by an enzyme known as calcineurin – a seemingly good guy in the bodily battle between good and bad proteins. However, Calcipressin1, the protein product of the DSCR1(Adapt78) gene, inhibits calcineurin from doing its regulatory job.
Consequently, long-term expression of this gene causes tau proteins to accumulate and form tangles. In contrast, short-term expression of gene DSCR1(Adapt78) prevents calcineurin from deactivating helpful enzymes used by cells to survive oxidative stress.
“More and more we are discovering the importance of genetic and cellular balance,” said Ermak. “In nature, many genes have multiple functions and work precisely at a specific level of expression. However, when these same genes are over- or under-expressed, problems arise.”
While debate still stirs over the true cause of Alzheimer’s disease, scientists agree that the trouble starts with the accumulation of two proteins in our brain: amyloid beta and tau.
While we all naturally produce these proteins, and small amounts are harmless, insoluble pieces build up in the brain when amyloid beta and tau are processed incorrectly. Some people produce these fragments faster than others, and, after decades of burden, the brain can no longer function.
As the disease runs its course, it replaces vital circuitry and healthy tissue in the brain with mounds of sticky, solid amyloid plaques and tangles of dead neurons.
By studying brain samples from patients who had died from Alzheimer’s disease, Davies and his team found the amount of tangles to be proportional to the chronic expression of Calcipressin1.
“In other words,” explained Davies, “more Calcipressin1 equaled more tangles.”
Interestingly, over-expression of DSCR1(Adapt78) is also associated with Down syndrome. The gene is found on chromosome 21, of which Down syndrome patients have one extra copy.
“The connection is probably explained by the fact that many of those born with Down syndrome will develop an early-onset form of Alzheimer’s disease,” said Davies.
The disease, first described in 1906 by German physician Alois Alzheimer, involves the degeneration of nerve cells in the cerebral cortex and hippocampus, restricted parts of the brain associated with memory.
The national Alzheimer’s Association estimates that the disease currently affects approximately 4 million Americans. By the year 2050, it is predicted that an additional 10 million could suffer from the disease.
With continued research and each new discovery, additional questions and ideas abound.
Davies, Ermak and their colleagues are now looking into the long-term effects of DSCR1(Adapt78) expression.
“We want to investigate whether chronic over-expression of this gene actually causes Alzheimer’s disease,” said Ermak.
“The findings here allow us to look into a number of other possibilities as well,” added Davies. “We’re now asking ourselves, ‘How exactly does this gene work? What turns it off and on? Since calcineurin is involved in immune responses, are DSCR1(Adapt 78) and Calcipressin1 capable of suppressing one’s immune system?’”
The right answers to such questions could potentially allow doctors to selectively turn on the gene in certain tissues, said Davies.
“If this gene were able to suppress one’s immune response, we could turn it on in a transplanted liver, for example, or turn it on in tissue surrounding that liver. We just don’t know yet. There’s a lot of work ahead of us.”
Contact Gia Scafidi at (213) 740-9335.