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

January 26, 2016
Credit: Human Brain Project

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 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.

So, scientists and drug developers have tried to ramp up . They hope that by cleaning that cellular junk up faster, they can keep it from causing symptoms.

Tiny change - big effects

The children's ataxia gene problem turned out to be not such a big deal genetically—it was such a slight mutation that it barely changed the way the cells made the protein. But that tiny change was enough to alter the autophagy process, and keep the children's brain and from working properly.

And that's where the yeast and Hungarian flies come in. Using them, the researchers could see what the children's problem gene did—and what that meant for the autophagy process. That's because the autophagy process is so important that organisms ranging from yeast to humans make almost exactly the same ATG5 protein—it's what scientists call "highly conserved" across species.

What they saw amazed them. The genetic mutation led cells to change just one link in the chain of amino acids that make up the ATG5 protein. The new amino acid even had the same electrical charge as the usual one. But that one changed link happened to be at the exact spot where ATG5 and its partner, called ATG12, connect to one another.

Since the two crucial autophagy partners couldn't link together as usual, the children's cells—and the yeast and flies' cells—couldn't clean up their cellular trash nearly as well. Autophagy didn't shut down completely, but less of it happened. And the fruit flies, like the children, had problems walking.

"This is a window into the autophagy system, and the first time where having less autophagy causes ataxia, developmental delays and ," says Margit Burmeister, Ph.D. the U-M neurogeneticist 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 lead to autophagy-related treatments.

Meanwhile, they're still working to understand how the change in ATG12-ATG5 binding actually changes autophagy. They're looking at cells made with the mutations from other ataxia patients to see if autophagy is also changed.

They're also looking for more families with ataxias. Each family could hold clues as important as the Turkish children's mutation did. In fact, Burmeister was in Turkey late in 2015 to work with colleagues to find more potential cases. Small villages with centuries of marriage among people with some relation to one another, and large families, can prove to be important to science.

The acceleration in genetic sequencing and other testing, made possible in the last decade by advances in technology and scientific methods, means they'll get closer to answers faster. What once took years can now be done in a single year. Having the expertise concentrated at U-M in genetics, , fruit fly biology, cell biology and more made the work go even faster, says Burmeister. U-M colleagues Daniel Klionsky, Jun Hee Lee and Jun Z. Li were critical to the new research. So were St. Jude colleagues led by Brenda Schulman who made X-ray images of the mutant ATG5 protein, and Zuhal Yapici and Aslihan Tolun, the colleagues in Istanbul and Gabor Juhasz in Budapest.

Explore further: Discovery reveals how protective immune cells protect themselves

More information: Myungjin Kim et al. Mutation in reduces autophagy and leads to ataxia with developmental delay , eLife (2016). DOI: 10.7554/eLife.12245

Related Stories

Discovery reveals how protective immune cells protect themselves

January 25, 2016
Researchers at St. Jude Children's Research Hospital have discovered the mechanism by which immune cells called regulatory T cells keep themselves intact and functional during their demanding task of holding the immune system ...

Discovery of protein that regulates cellular recycling yields new drug targets

June 2, 2014
Researchers at the University of Michigan have discovered a key regulator of autophagy, the cellular recycling process involved in many human diseases. The finding illuminates potential new drug targets for cancer, neurodegeneration ...

New evidence in mice that cocaine makes brain cells cannibalize themselves

January 18, 2016
Working with mice, researchers at Johns Hopkins have contributed significant new evidence to support the idea that high doses of cocaine kill brain cells by triggering overactive autophagy, a process in which cells literally ...

Eye's recycling process key to seeing color, bright light

October 28, 2015
As many of us learned in high school science class, the retina's rods and cones allow us to see. Rods are for night vision, and cones operate in bright light and allow us to distinguish colors. But although scientists have ...

Calcium channels play a role in neuronal homeostasis and elimination of toxic buildup of proteins

March 26, 2015
Taking out the garbage is a crucial step in housecleaning. Similarly, autophagy is the body's first-line of defense against the buildup up of toxic substances, degrading old organelles and proteins to provide new substrates ...

Study shows GATA4 plays a key role in cell senescence

September 25, 2015
(Medical Xpress)—A team of researchers from Harvard Medical School and Buck Institute for Research on Aging has conducted a study that has revealed that GATA4 (a transcription factor) plays a significant role in cell senescence. ...

Recommended for you

Hibernating ground squirrels provide clues to new stroke treatments

November 17, 2017
In the fight against brain damage caused by stroke, researchers have turned to an unlikely source of inspiration: hibernating ground squirrels.

Age and gut bacteria contribute to multiple sclerosis disease progression

November 17, 2017
Researchers at Rutgers Robert Wood Johnson Medical School published a study suggesting that gut bacteria at young age can contribute to multiple sclerosis (MS) disease onset and progression.

Molecular guardian defends cells, organs against excess cholesterol

November 16, 2017
A team of researchers at the Harvard T. H. Chan School of Public Health has illuminated a critical player in cholesterol metabolism that acts as a molecular guardian in cells to help maintain cholesterol levels within a safe, ...

Prototype ear plug sensor could improve monitoring of vital signs

November 16, 2017
Scientists have developed a sensor that fits in the ear, with the aim of monitoring the heart, brain and lungs functions for health and fitness.

Ancient enzyme could boost power of liquid biopsies to detect and profile cancers

November 16, 2017
Scientists are developing a set of medical tests called liquid biopsies that can rapidly detect the presence of cancers, infectious diseases and other conditions from only a small blood sample. Researchers at The University ...

FDA to crack down on risky stem cell offerings

November 16, 2017
U.S. health authorities announced plans Thursday to crack down on doctors pushing stem cell procedures that pose the gravest risks to patients amid an effort to police a burgeoning medical field that previously has received ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.