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Scientists show how defects in blood-brain barrier could cause neurological disorder

First 'Disease in a dish' model of Allan-Herndon-Dudley Syndrome may shed light on common neurological diseases

Date:
May 16, 2017
Source:
Cedars-Sinai Medical Center
Summary:
Scientists for the first time have assembled a 'disease in a dish' model that pinpoints how a defect in the blood-brain barrier can produce an incurable psychomotor disorder, Allan-Herndon-Dudley syndrome. The findings point to a path for treating this syndrome and hold promise for analyzing other neurological diseases.
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Scientists for the first time have assembled a "disease in a dish" model that pinpoints how a defect in the blood-brain barrier can produce an incurable psychomotor disorder, Allan-Herndon-Dudley syndrome. The findings point to a path for treating this syndrome and hold promise for analyzing other neurological diseases.

The blood-brain barrier, formed by blood vessels, protects the brain from toxins circulating in the body's blood system. It also can keep out therapeutic drugs and, when defective, biomolecules that are needed for healthy brain development. The latter is what happens in Allan-Herndon-Dudley syndrome, according to investigators from Cedars-Sinai and the University of Wisconsin-Madison. The rare, congenital syndrome causes cognitive disability, impaired speech and underdeveloped muscles, among other symptoms.

Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, said the model developed by the collaborative team's study, published May 16 in the journal Cell Stem Cell, may shed light on other neurological conditions that involve possible dysfunctions in the blood-brain barrier. These conditions include Alzheimer's disease and Huntington's disease, which together affect millions worldwide. A related paper, involving Svendsen, his colleague Gad Vatine, PhD, and a team from University of California, Irvine, published the same day in the journal Cell Reports, used a similar approach to study Huntington's disease.

"This model could have far-reaching implications to advance the understanding and treatment of neurological disorders," said Svendsen, senior author of the Cell Stem Cell study.

To develop their "disease in a dish" model, the team took skin cells from patients with Allan-Herndon-Dudley syndrome and reprogrammed them into induced pluripotent stem cells, which then can be developed into any type of tissue in the body. Using these cells, the team modeled the patients' neurons and blood-brain barrier in a laboratory dish.

"To our surprise, the neurons were normal," said Vatine, a postdoctoral scientist in Svendsen's laboratory and first author of the study. "But the blood-brain barrier was not."

The dish model showed that the thyroid hormone, which is critical to neuron development, wasn't getting into the brain. This hormone requires a biomolecule to transport it across the blood-brain barrier. Due to a gene mutation in Allan-Herndon-Dudley patients, there was not enough of the biomolecule in the barrier to do the job.

"The blood-brain barrier forms pretty early in gestation, so the thyroid hormone, even from the mother, is probably not getting through the barrier and into the brain, likely leading to developmental deficits," said Eric Shusta, a professor of Chemical and Biological Engineering at the University of Wisconsin-Madison and a senior author of the study.

One potential way to treat Allan-Herndon-Dudley syndrome, based on this model, may be to develop an artificial version of the thyroid hormone that does not need the biomolecule to cross the blood-brain barrier, Vatine said. It also may be possible in the future to repair the gene mutation using gene-editing technology, which the investigators were able to do in the laboratory dish, he added.


Story Source:

Materials provided by Cedars-Sinai Medical Center. Note: Content may be edited for style and length.


Journal Reference:

  1. Gad D. Vatine, Abraham Al-Ahmad, Bianca K. Barriga, Soshana Svendsen, Ariel Salim, Leslie Garcia, Veronica J. Garcia, Ritchie Ho, Nur Yucer, Tongcheng Qian, Ryan G. Lim, Jie Wu, Leslie M. Thompson, Weston R. Spivia, Zhaohui Chen, Jennifer Van Eyk, Sean P. Palecek, Samuel Refetoff, Eric V. Shusta, Clive N. Svendsen. Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier. Cell Stem Cell, 2017; 20 (6): 831 DOI: 10.1016/j.stem.2017.04.002

Cite This Page:

Cedars-Sinai Medical Center. "Scientists show how defects in blood-brain barrier could cause neurological disorder." ScienceDaily. ScienceDaily, 16 May 2017. <www.sciencedaily.com/releases/2017/05/170516171250.htm>.
Cedars-Sinai Medical Center. (2017, May 16). Scientists show how defects in blood-brain barrier could cause neurological disorder. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2017/05/170516171250.htm
Cedars-Sinai Medical Center. "Scientists show how defects in blood-brain barrier could cause neurological disorder." ScienceDaily. www.sciencedaily.com/releases/2017/05/170516171250.htm (accessed March 28, 2024).

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