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Mutation in common protein triggers tangles, chaos in brain cells

A pioneer in the study of neural cells revealed today (October 23, 2018) how a single mutation that affects the…

A pioneer in the study of neural cells revealed today (October 23, 2018) how a single mutation that affects the most common protein in a supporting brain cell produces devastating fibrous globs. These, in turn, interfere with the location of cellular treatment units, damage the flow of energy and signals through the brain and reduce the formation of myelin, a major neuron isolator.

Su-Chun Zhang, professor of neuroscience at the University of Wisconsin-Madison, a doctor and doctoral researcher, looked at astrocytes, which differ from signal transmitting neurons, but play several roles in the brain. Astrocytes consist of 20 to 40 percent of the cells in the brain.

Named for its star form, these astrocytes – derived from human stem cells – show their structural protein, GFAP, in red. DNA in the cell nucleus appears blue. Courtesy of Jeffrey Jones

Astrocytes in the study were grown from adult cells that were converted to stem cells. The adult cells were donated by the families to two patients with the Alexander disease, a rare, fatal genetic disorder.

When grown in a lab bowl, astrocytes showed the signs of Alexander, including tangles built from a protein called GFAP, and

GFAP, or glialfibrillary acid protein, is a cytoskeletal protein that gives astrocyte its distinctive star-like form.

When the stem cells which were the source of the astrocytes corrected with redirection, the astrocytes derived from the manipulated stem cells resulted in no signs of the Alexander disease.

After decades of emphasizing the role of neurons, astrocytes and other glial cells will be more focused on their important contribution to neuron’s health – and their role in disease.

When the stem cells that were the source of the astrocytes were corrected with redecoration, the astrocytes were su

Alexander disease is fortunately extremely rare, says Zhang, but rare diseases are important for neuroscience. “We often grow to understand a disease process through rare diseases. A mutation discovery in a family with Lou Gehrig’s disease led to the discovery of ALS basic pathogens, and the same applies to Parkinson’s and Alzheimer’s.”

Through studies by co-author Albee Messing, a professor emeritus of comparative biosciences, and others at UW-Madison, Alexander has been linked to a mutation in the GFAP gene, “which encodes a protein that is very common in astrocytes,” said Zhang.

GFAP is so common that astrocytes are identified by their presence, said Zhang. “GFAP was a major player for some reason, but no-one knew the wide range of effects until today.”

Photo: Jeff Miller

The study, published today in Cell Reports, describes how Zhang, with first author Jeffrey Jones, now a postdoctor at the Salk Institute, and others, used cell cultures to track the role of GFAP mutation in the Alexander disease.

Alexander disease, a decades long focus on Messing’s research, provided an ideal keyhole for studying the most common protein in astrocytes, “said Zhang.” But after 20 years, we still had not wondered how mutant GFAP caused this fatal disease. “

Although common in astrocytes, GFAP is not present in other cell types.

The damage seems to begin with aggregated filaments inside the astrocytes that cause widespread tangles and are likely to trigger a major disruption in cellular subunits that produce proteins, process energy and store chemicals. “The organelles – mitochondria, endoplasmic reticulum and lysosomes – were all distributed abnormally,” said Zhang, “and it was a clue that GFAP is crucial for leading organelles to their correct places.”

After decades of emphasizing the role of neurons, astrocytes and other glial cells, they are more focused on their important contribution to neuron’s health – and their role in disease.

There are no immediate clinical consequences, but the impact of the study can still be wide, says Zhang. “This protein changes in astrocytes in Alexander and virtually every single neurological disorder, including Alzheimer’s, Parkinson’s, Huntingtons, ALS, and autism.”

Growing human brain cells in lab boards was the key to the results. Zhang was the first researcher who transformed all-purpose human stem cells into neural cells. He has since learned to distinguish these stem cells into a wide range of brain cells, including neurons, the classic signal carriers and the “helper cells” as astrocytes.

Astrocytes perform a large number of functions, such as supportive cells in the blood-brain barrier, provide nutrients, control the balance of calcium ions, and help with myelin isolation for neurons.

Zhang used laboratory falsified human brain cells could avoid complications that involved animal studies. “For Alexander, like any other disease, we have used flies, mice and rats. When we express the mutant protein, the protein becomes aggregated instead of wireless. But with animals we always have a problem, because when we change the protein content, the cells will naturally react. But the exact relationship to the disease is a question mark. “

Growing human brain cells in lab boards was the key to the results. Zhang was the first researcher who transformed all-purpose human stem cells into neural cells.

Using human cells with the real mutation is somewhat uncertain, said Zhang and using CRISPR-Cas-9 redirect to reverse the injury further demonstrated the importance of the GFAP mutation.

He basically adds, “We saw something that we did not expect, that the mutation created problems for molecular trade” that concern molecules in, through and out of the cells. The mutation also damaged a signal system based on the movement of calcium ions.

A mutation has deep effects, he says. “Without the correct traffic system, molecules can not move in and out of the cell correctly, so the cell can not do its job. GFAP is basic. And when we corrected the mutation, the cells looked normal.”

GFAP, he stresses, “is the most abundant protein in astrocytes, and we already knew that it changed in almost all neurological states. As you understand how the Alexander disease occurs, we are even more excited about the basic biology. “

This study was partially supported by Eunice Kennedy The National Institute of Child Health and Human Development (NICHD) (HD076892 and U54 HD090256), NIH-National Institute of Mental Health (NIMH) (MH099587 and MH100031), NIH-National Institute of Neurological Disorders and Stroke (NINDS) (NS076352, NS086604 and NS096282), the Bleser Family Foundation, and the Busta Foundation. Su-Chun Zhang acknowledges the Steenbock professor.

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