Stem Cell Model Uncovers Mechanisms Underlying Disease Pathology of Alexander Disease

Mechanisms underlying the disease pathology of Alexander disease, a rare leukodystrophy affecting the nervous system, have been uncovered by City of Hope investigators. Through use of a new stem cell model of the disease, the team identified a potential therapeutic target for Alexander disease and other neurodegenerative diseases.

The team chose to study Alexander disease due to its similarity to other neurodegenerative diseases—such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS)—and the insight it might provide upon evaluation. The team also chose Alexander disease for its simple pathology.

The disease is caused by mutations in the astrocytic filament gene GFAP that inhibits a type of precursor cell that later becomes myelin, the fatty sheath that coordinates communication within the brain's network. Although astrocytes are thought to play a role in controlling myelination, the study authors noted that because Alexander disease animal models do not recapitulate critical myelination phenotypes, just how these astrocytes contribute to leukodystrophy remains unclear.

"The bulk of ApoE4 resides in astrocytes; ApoE4 is a gene variant known for increasing the risk of Alzheimer's disease," Yanhong Shi, PhD, senior author of the study and director of the Division of Stem Cell Biology at City of Hope, explained in a recent statement. "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."

Since previous investigators were unable to create an animal model to observe the disease pathway of Alexander disease, Dr. Shi and her team created a stem cell model; her team also created a platform to evaluate therapeutic interventions for related neurodegenerative diseases.

For the stem cell model, the team created patient-derived stem cells that harbored a mutation in the GFAP gene. They compared their model with brains from Alexander disease patients and noted that Rosenthal fibers, disease-associated protein deposits, were present in both models.

The team used CRIPSR/Cas9 gene editing to correct the GFAP mutation in diseased astrocytes which resulted in a reduced amount of disease-associated protein deposits. They then used the stem cell model to gain insight into how Alexander disease develops.

In this disease, astrocytes hinder the growth of precursor cells that later become myelin and speed up the brain’s communication network. The investigators compared the various genes expressed in the astrocytes that had been derived from the stem cells of Alexander disease patients with those from healthy controls and observed that GFAP mutant astrocytes produce a neuroinflammation marker, a protein referred to as CHI3L1, which suppresses processes associated with neural development, including myelination.

As such, Dr. Shi concluded that Alexander's disease or leukodystrophic diseases that decrease myelin may be treatable with therapies that target CHI3L1.

“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,” Dr. Shi added. “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.”