Public Release: 

New stem cell model can be used to test treatments for a rare nervous system disorder

The study provides insight into how to treat other neurodegenerative conditions, including Alzheimer's disease, City of Hope researcher says

City of Hope


IMAGE: An Alexander disease patient's stem cell-derived astrocytes (green) inhibits the growth of precursor cells that become myelin and speed up the brain's communication network. view more 

Credit: Yanhong Shi/City of Hope

DUARTE, Calif. -- A City of Hope researcher has developed a stem cell model to assess possible treatments for a rare nervous system disorder that is in the same disease group as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS).

The finding takes Yanhong Shi, Ph.D., senior author of the study, and her colleagues one step closer to finding a way to slow or treat Alzheimer's disease and other neurodegenerative disorders.

The team studied Alexander disease because of its relatively simple pathology. In Alexander disease, a mutation in a glial cell called astrocytes inhibits a type of precursor cell that later becomes myelin, the fatty sheath that facilitates communication within the brain's network.

"The bulk of ApoE4 resides in astrocytes; ApoE4 is a gene variant known for increasing the risk of Alzheimer's disease," said Shi, director of the Division of Stem Cell Biology at City of Hope. "So if we understand how astrocytes function, then we can develop therapies to treat Alexander disease and perhaps other diseases that involve astrocytes, such as Alzheimer's and ALS."

The study, published on Aug. 2 in the journal Cell Stem Cell, reports to be the first to overcome a significant challenge for understanding how mutations in a gene found in astrocytes called GFAP inhibits normal myelin distribution.

Previously, scientists were not able to create an animal model to observe the disease path. So, Shi, Li Li, lead author of the study and a graduate student in the Shi Lab, and their colleagues created a stem cell model that provides insight into the disease pathway of Alexander disease. They also created a platform for assessing therapeutic interventions for related neurodegenerative diseases.

The researchers created patient-derived stem cells that harbor a mutation in the GFAP gene. They did a side-by-side comparison with brains obtained from Alexander disease patients and noted that both models exhibit disease-associated protein deposits called Rosenthal fibers.

The researchers used CRIPSR/Cas9 gene editing to correct the GFAP mutation in diseased astrocytes and found that the correction of the GFAP mutation reduced disease-associated protein deposits. Next, they examined how Alexander disease develops using this newly discovered stem cell disease model.

In Alexander disease, astrocytes inhibit the growth of "oligodendrocyte progenitor cells," precursor cells that later become myelin and speed up the brain's communication network. By comparing the different genes expressed in the astrocytes derived from stem cells of Alexander disease patients and those of healthy controls, the researchers found that GFAP mutant astrocytes secrete the protein CHI3L1, a marker of neuroinflammation that suppresses neural development-related processes, including myelination.

Therapies that target CHI3L1 may be able to treat Alexander's disease or leukodystrophic diseases that decrease myelin, Shi said.

"Although neurons have been in the spotlight for years, more studies are finding that astrocytes play a very important role in normal brain function and neurological disease," Shi said. "Astrocytes make up a large proportion of the cells in the brain and are important in neuroinflammation. Chronic inflammation creates disease. The question is how to prevent it."


Researchers at the Diabetes & Metabolism Research Institute at City of Hope, Beckman Research Institute of City of Hope, New York Stem Cell Foundation Research Institute, the New York Genome Center, New York University and Massachusetts Institute of Technology also contributed to this study, which was supported by the Herbert Horvitz family, Sidell-Kagan Scientific & Medical Research Foundation, California Institute for Regenerative Medicine, National Institute of Aging - a part of the National Institutes of Health - Sidney Kimmel Foundation, Melanoma Research Alliance, National Human Genome Research Institute and National Cancer Institute.

About City of Hope

City of Hope is an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as one of only 49 comprehensive cancer centers, the highest recognition bestowed by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network, with research and treatment protocols that advance care throughout the world. City of Hope's main campus is in Duarte, California, just northeast of Los Angeles, with additional locations throughout Southern California. It is ranked as one of "America's Best Hospitals" in cancer by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation, diabetes and numerous breakthrough cancer drugs based on technology developed at the institution. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.

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