A pioneer in the study of neural cells revealed how a single mutation affecting the most common protein in a supporting brain cell produces devastating, fibrous globs. These, in turn, disturb the location of cellular processing units, harm the flow of energy and signals through the brain, and reduce the formation of myelin, an essential insulator for neurons.

Researchers looked at astrocytes, which are distinct from the signal-transmitting neurons, but play multiple roles in the brain. Astrocytes comprise 20 to 40 percent of cells in the brain.

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

Once grown in a lab dish, the astrocytes showed the hallmarks of Alexander, including tangles built of a protein called GFAP, and errant locations of mitochondria and other cellular processing units.

GFAP, or glial fibrillary acidic protein, is a cytoskeleton protein, giving the astrocyte its distinctive star-like shape.    

When the stem cells that were the source of the astrocytes were corrected with gene editing, the astrocytes subsequently derived from the engineered stem cells showed no signs of Alexander disease.

After decades of emphasizing the role of neurons, astrocytes and other glial cells are coming into greater focus for their essential contributions to the health of neurons - and for their role in disease..

Alexander disease, a decades-long focus of Messing's research, provided an ideal keyhole to study the most common protein in astrocytes, the senior author says, "but after 20 years, we still had not figured out how the mutant GFAP caused this fatal disease."

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

The damage seems to start with aggregated filaments inside the astrocytes that cause widespread tangles and likely trigger a broad disturbance in cellular subunits that produce proteins, process energy and store chemicals. "The organelles -- the mitochondria, endoplasmic reticulum and lysosomes -- were all distributed abnormally," the senior author says, "and that was a clue that GFAP is critical for guiding organelles to their correct locations."

There are no immediate clinical implications, but the study's impact could nevertheless be broad, the author says. "This protein is altered in astrocytes in Alexander, and virtually every single neurological disorder, including Alzheimer's, Parkinson's, Huntington's, ALS and autism.".

Using human cells with the real-world mutation sidesteps some uncertainty, the author says, and using CRISPR-Cas-9 gene editing to reverse the damage further proved the importance of the GFAP mutation.

Broadly speaking, the author adds, "we saw something we did not expect, that the mutation created problems for the molecular trafficking system" that moves molecules in, through and out of the cells. The mutation also harmed a signaling system based on movement of calcium ions.

One mutation, thus, has profound effects, the author says. "Without the correct traffic system, molecules cannot move in and out of the cell correctly, and so the cell cannot do its job. GFAP is fundamental. And when we corrected the mutation, the cells looked normal."

GFAP, the author stresses, "is the most abundant protein in astrocytes, and we already knew it's altered in nearly all neurological conditions. While understanding how Alexander disease occurs is important, we're even more excited by the fundamental biology."

https://news.wisc.edu/mutation-in-common-protein-triggers-tangles-chaos-inside-brain-cells/

https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31543-2