Research identifies a molecular basis for common congenital brain defect

Dec 13, 2016

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have discovered a molecular cause of hydrocephalus. Because the same molecule is also implicated in Down syndrome, the finding, published today in the Journal of Neuroscience, may explain the 10-fold increased risk of hydrocephalus in infants born with Down syndrome.

"We found that deleting the gene for sorting nexin 27, or SNX27, which plays a major role in the development of Down's syndrome, causes hydrocephalus," said Huaxi Xu PhD, the Jeanne and Gary Herberger Leadership Chair of SBP's Neuroscience and Aging Research Center. "The mechanism we uncovered likely only accounts for a fraction of hydrocephalus cases, but we identified potential non-surgical treatments for these cases that deserve further study."

The new study followed up on prior results from Xu's lab showing that SNX27, a protein that regulates traffic of other proteins within cells, is found at lower than normal levels in the brains of individuals with Down syndrome. They also found that inactivating the gene for SNX27 in mice causes learning and memory problems similar to those in Down syndrome.

Here, Xu's team looked at overall brain development in mice without SNX27. They observed severe hydrocephalus, with fluid-filled ventricles in the brain that were much larger than normal. Examining potential causes, they saw that these mice lacked the cells that normally line the ventricles and circulate fluid in the brain--the ependymal cells.

The researchers also determined why ependymal cells aren't generated--without SNX27, brainstem cells generate too much of the active form of a protein called Notch that keeps them from becoming ependymal cells. The active form of Notch is created by the enzyme gamma-secretase, whose activity is regulated by SNX27. Without SNX27, too much gamma-secretase remains active.

"Proper flow of fluid out of the brain isn't just crucial in brain development--it also helps eliminate toxic proteins such as amyloid beta, which causes Alzheimer's," added Xu. "Since we've already shown that lack of SNX27 increases production of amyloid beta, genetic variants that cause lower than normal levels of SNX27 would greatly increase risk for Alzheimer's. This double effect likely explains why Down's syndrome patients' brains exhibit Alzheimer's pathology by adulthood."

Wang, Xu, and their collaborators went on to show that giving either a drug that inhibits gamma-secretase to SNX27-deficient mice prevents them from developing hydrocephalus.

"Gamma-secretase inhibitors could be a future treatment for cases of hydrocephalus caused by ependymal cell defects," commented Xu. "However, further study is required to determine whether this approach is relevant to humans."

This research was performed in collaboration with scientists at Xiamen University in China and the Institute of Molecular and Cell Biology in Singapore. Funding was provided by the National Natural Science Foundation of China, the Thousand Young Talents Program of China, the Fundamental Research Funds for the Chinese Central Universities, the National Institutes of Health, the Alzheimer's Association, the Global Down Syndrome Foundation, the BrightFocus Foundation, and the Cure Alzheimer's Fund.

Source: News Release
Sanford-Burnham Prebys Medical Discovery Institute 
December 13, 2016