Researchers Gain New Insights into Alexander Disease Mortality Based on Protein Analysis

By Caitlin Seida from In The Cloud Copy

Although it’s already known that the cause of Alexander disease (AxD), a type of leukodystrophy, is a misfolded protein known as GFAP. It was unknown why some individuals with Alexander disease live long lives while others die in childhood or even infancy. New research suggests that chemical changes that trigger damage to the protein help predict the age of onset of symptoms, as well as the age of mortality.

While the changes have previously been observed in the astrocytes – a type of glial cell in the brain – of those living with AxD, the study, published in the November 4, 2019 journal eLife is the first of its kind to demonstrate changes in vitro, or outside of the human body and in a laboratory setting.

What is Alexander Disease?

Alexander disease is not an inherited disorder – it’s generally accepted that the disease occurs because GFAP proteins collect in specialized brain cells called astrocytes. Like other forms of leukodystrophy, those living with AxD eventually face a loss or cessation of nervous system function.

As the defective proteins increase in number and gather in a person’s astrocytes, these cells weaken and deteriorate, eventually ceasing to function altogether. Astrocytes’ main purpose in the body is to support other brain and spinal cord cells to keep them healthy.

In the majority of people with Alexander disease, symptoms are present from birth through before age two. In those with an infant onset, symptoms are most pronounced due to an enlarged brain. Infants with AxD experience seizures, stiff limbs and developmental delays.

Others with AxD don’t have an onset by age 2 and may develop the leukodystrophy later in life – in childhood or even adulthood. When the onset is later, people living with the disease start to notice problems with their speech, trouble swallowing, seizures, and a loss of coordination. In those who have adult-onset Alexander disease, symptoms can mimic or be mistaken for MS or Parkinson’s disease.

Purpose and Focus of the Study

Lead researcher Natasha Snider, PhD and her colleagues have been studying Alexander disease since 2011. They sought to examine the GFAP protein accumulation and perhaps find an extant drug that might help those living with Alexander disease or discover the necessary insights to create a new treatment or therapy.

Using the knowledge that an accumulation of misfolded GFAP proteins is a potential cause, they further looked at the mechanism of action that leads to the onset of AxD. As the number of defective GFAP cells increases, astrocytes fail to perform as necessary – harming neural and non-neural cells in those with Alexander disease. This accumulation of toxic GFAPs is not exclusive to AxD – but it is also seen in other diseases like giant axonal neuropathy and astrocytoma tumors.

Study Methods and Findings

The findings published in eLife were based on the use of mass spectrometry analysis of brain tissue in samples that both did and did not have Alexander disease. Snider and her team introduced pluripotent stem cells, or “master cells,” and gene editing technology to the samples to help identify relevant markers to the disease and the changes in cell biology.

The team used a cell line model created by graduate student Rachel Battaglia and assistant professor of pharmacology at UNC, Adriana Beltran, PhD. They noted that the defective proteins gathered outside the cell nuclei. And although this phenom has been seen in the astrocytes of patients living with Alexander disease, the study is the first of its kind to create and replicate the methods by which it occurs independent of the human body in a lab setting.

For the first time, researchers were able to identify disease severity markers present in cells. A molecular difference between children with Alexander disease who experience death earlier in life and those who live for far longer – up to or surpassing several decades – was noted as a result of the study.

Study Implications

The study illustrates how these defective proteins accumulate in other cellular organelles to cause the progress of Alexander disease; the results may not be exclusive to this illness or leukodystrophy in general. Previously published literature on filament proteins – of which GFAP is a part – point to the potential value of the research in treating other diseases in which filament proteins are damaged or defective.

Because the study linked the accumulation of GFAP proteins to the age of onset and age of death in those living with Alexander disease, the next step in research may very well be to see if the molecular cause or markers of the protein accumulation can be changed to create a new treatment or therapy for those living with this rare form of leukodystrophy.


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