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The Molecular basis for hydrocephalus

Sorting nexin 27 (SNX27) is a molecule that tags specific proteins to be transferred out of the brain. It appears at lower volume in infants born with hydrocephalus, and is also implicated in Down's syndrome.

SNX27 molecular research just published may explain why there is a ten-fold increase in risk for hydrocephalus in infants with Down's. Although a fairly common birth defect, hydrocephalus can be potentially life-threatening. Fluid surrounding the brain not tagged by SNX27 for removal out of the brain, accumulates and enlarges the brain.

Hydrocephalus affects one or two of every 1,000 births. Some causes are known to be due to several well-characterized brain and skull malformations that block fluid outflow. But, it can also begin without obvious abnormalities.

The work appears in the Journal of Neuroscience.

Treatment for hydrocephalus includes a surgically inserted shunt to divert fluid accumulating in the brain to another part of the body, where it can be absorbed. However, these tubes can get infected, and about half the time they fail and need replacement. Symptoms include headaches, vomiting, fever and irritability until the shunt is replaced.

"We also found that deleting the gene for sorting nexin 27, or SNX27, plays a major role in causing hydrocephalus in Down's syndrome.The mechanism we uncovered likely only accounts for a fraction of hydrocephalus cases, but we have identified potential non-surgical treatments for these cases that deserve further study."

Huaxi Xu, PhD, the Jeanne and Gary Herberger Leadership Chair of SBP's Neuroscience and Aging Research Center.

Huaxi Xu's laboratory works on mice as a model system to study brain development. Some of their previous work revealed SNX27 to be a regulator of protein traffic flow in and out of brain ependyma cells, called ependymocytes, a type of glial cell. Ependymocytes line the cerebrospinal fluid filled ventricles in the brain and the central canal of the spinal cord.

Researchers observed severe hydrocephalus, where these ventricles are much larger than normal, in mice without the gene to produce SNX27. They also saw that these mice lacked the ependymal cells normally lining ventricles that circulate fluid throughout the brain. The mice also exhibited learning and memory problems similar to those seen in Down's.

Xu's team then determined why ependymal cells weren't being generated. Without SNX27, brain stem cells generate too much of the active form of a protein called Notch which keeps the stem cells from becoming ependymal cells. Notch is created by an enzyme called gamma-secretase, which 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.

"Since we've already shown that lack of SNX27 increases production of amyloid beta, [it would appear] genetic variants that cause lower than normal levels of SNX27 would [also] greatly increase risk for Alzheimer's.

"This double effect likely explains why Down's syndrome patients' brains exhibit Alzheimer's pathology by adulthood."

Huaxi Xu, PhD

Wang, Xu, and their collaborators went on to show giving 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. However, further study is required to determine whether this approach is relevant to humans."

Huaxi Xu, PhD

Hydrocephalus is a brain disorder derived from CSF accumulation due to defects in CSF clearance. Although dysfunctional apical cilia in the ependymal cell layer are causal to the onset of hydrocephalus, mechanisms underlying proper ependymal cell differentiation are largely unclear. SNX27 is a trafficking component required for normal brain function and was shown previously to suppress γ-secretase-dependent amyloid precursor protein and Notch cleavage. However, it was unclear how SNX27-dependent γ-secretase inhibition could contribute to brain development and pathophysiology. Here, we describe and characterize an Snx27-deleted mouse model for the ependymal layer defects of deciliation and hydrocephalus. SNX27 deficiency results in reductions in ependymal cells and cilia density, as well as severe postnatal hydrocephalus. Inhibition of Notch intracellular domain signaling with γ-secretase inhibitors reversed ependymal cells/cilia loss and dilation of lateral ventricles in Snx27-deficient mice, giving strong indication that Snx27 deletion triggers defects in ependymal layer formation and ciliogenesis through Notch hyperactivation. Together, these results suggest that SNX27 is essential for ependymal cell differentiation and ciliogenesis, and its deletion can promote hydrocephalus pathogenesis.

Down's syndrome (DS) in humans and mouse models has been shown previously to confer a high risk for the development of pathological hydrocephalus. Because we have previously described SNX27 as a component that is consistently downregulated in DS, we present here a robust Snx27-deleted mouse model that produces hydrocephalus and associated ciliary defects with complete penetrance. In addition, we find that γ-secretase/Notch modulation may be a candidate drug target in SNX27-associated hydrocephalus such as that observed in DS. Based on these findings, we anticipate that future study will determine whether modulation of a SNX27/Notch/γ-secretase pathway can also be of therapeutic interest to congenital hydrocephalus.

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.

About SBP
Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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Dec 29, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

SNX27, or 'sorting nexin 27' protein, regulates traffic of other proteins in cells.
It is found at lower than normal levels in the brains of individuals with
Down's syndrome and causes hydrocephalus of the brain.
Image Credit: Pinterest



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