Breaking the brain's garbage disposal: Study shows even a small problem causes big effects

You wouldn’t think that two Turkish children, some yeast and a bunch of Hungarian fruit flies could teach scientists much. But in fact, that unlikely combination has just helped an international team make a key discovery about how the brain’s “garbage disposal” process works—and how little needs to go wrong in order for it to break down.
The findings show just how important a cell-cleanup process called autophagy is to our brains. It also demonstrates how even the tiniest genetic change can have profound effects on such an essential function.

The new understanding could lead to better treatments for people whose brain and nerve cells have troubles “taking out the trash.” Some such drugs already exist, but more could follow.

Following a mystery to its end

In a new paper in the online journal eLife, the team describes their painstaking effort to figure out what was wrong in the Turkish siblings, and to understand what it meant. The children have a rare condition called ataxia that makes it harder for them to walk. They also have intellectual disability and developmental delays.

Ataxia is rare—affecting about one in every 20,000 people—and can cause movement problems in people who develop it in adulthood, or a range of symptoms when it arises in children.

Because researchers from the University of Michigan Medical School had published studies about families with multiple cases of ataxia before, Turkish researchers got in touch with them when the children’s parents brought them in for treatment.

That started a long chain of scientific sleuthing that led to today’s publication. First, the U-M team studied samples of the children’s DNA, and used advanced methods to pinpoint the exact genetic mutation that caused their symptoms.

It turned out to be on one of the genes that scientists know play a key role in autophagy, called ATG5. Cells throughout the body trigger their internal garbage crews by turning on this gene and its partners, and using them to make proteins that help clean up the cell.

The junk that these garbage crews clean up includes botched proteins—ones that have been used up or weren’t made right in the first place.

In fact, many forms of ataxia (and lots of other diseases) are caused by genetic problems that result in brain and nerve cells making such damaged, misfolded proteins. The proteins build up inside cells, killing them and causing neurological problems.

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Flies, showing signs of ataxia, who would have thought it:-)xB