Brain waste: X-ray assistance

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  • Published: Feb 1, 2016
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Brain waste: X-ray assistance

Brain cell cleanup

Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay Credit: eLife, Burmeister et al)

The cellular cleanup process known as autophagy is essential to brain health. New genetic studies, supported by X-ray structural studies, now reveal how even the smallest genetic change can have profound effects on this critical function. The research might lead to improved treatments for ataxia and other conditions that seemingly arise because of garbage disposal problems in the brain.

Researchers from the University of Michigan Medical School had published studies about families with multiple cases of ataxia that provided the first clues. Ataxia is rare, affecting about one in every 20 000 people, it gives rise to movement problems in adulthood but there can be additional motor and mental developmental symptoms if it arises in children. Researchers in Turkey had puzzled over siblings presented to healthcare workers with a particular form of the condition. The earlier published work led the team in Turkey to a collaboration with the Michigan scientists. First, the U-M team studied samples of the children's DNA and looked for the precise genetic mutation that had given rise to their symptoms. It was apparent that one of the genes involved was one known to play a key role in autophagy. The gene ATG5 is switched on in cells along with other genes to make proteins that act as the internal waste removal system. The rubbish they remove includes other proteins that were not built properly or are misfolded.

Misfolded problems

Numerous disorders exist wherein misfolded proteins and the cell's failure to dispose of them is the underlying cause of the symptoms. The misfolded proteins accumulate inside cells, eventually killing them and if those cells are neurones then the problem leads to neurological problems. Scientists and drug developers have previously tried to boost autophagy activity in the hope of cleaning up cells in which misfolded proteins have accumulated to eradicate or subdue symptoms.

The first part of the study revealed that the siblings' ataxia was caused by a seemingly small genetic change, a single mutation that did not change how the cells made the cleanup protein much at all. But the tiny change was enough to break the autophagy process, and keep the children’s brain and nerve cells from working properly. In order to obtain a clearer picture of why such a small genetic change could cause such a big problem the team turned to yeast and Hungarian flies. Using these organisms, they could reveal what the gene does because the same gene is present in those species too in a "highly conserved" state across species.

Familial clues

The genetic mutation changes just one amino acid in the ATG5 protein but it changes it at a critical position in the protein chain, the site where X-ray crystallography showed that ATG5 hooks up with its work partner ATG12. In blood cells of the children, indeed, the authors showed that the ATG-ATG12 complex was not formed efficiently. Without this critical link, autophagy fails.

"This is a window into the autophagy system, and the first time where having less autophagy causes ataxia, developmental delays and intellectual disability," explains Michigan neurogenetecist Margit Burmeister who led the research and is co-senior author on the new paper. "It's a subtle change, but it shows how important autophagy is in neurological disorders." Burmeister and colleagues from the University of Michigan, St. Jude Children’s Research Hospital, Howard Hughes Medical Institute, Istanbul University and Bogazici University in Istanbul and Eötvös Loránd University in Budapest hope the findings will lead to new ways to treat autophagy problems.

They are now working to understand how the change in ATG12-ATG5 binding actually changes autophagy, because the mutation does not shut down autophagy entirely, just enough to cause problems. They are looking at cells made with the mutations from other ataxia patients to see if autophagy is also changed. The team is also looking for more families with various forms of ataxia, and is investigating if reduced autophagy also plays a role when common forms of ataxia are caused by abnormal protein aggregates that might just overload the autophagy system. Genetic clues from families in isolated communities could prove very useful, but they are also looking at other families, Burmeister told SpectroscopyNOW.

Related Links

eLife 2016, online: "Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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