TO WEB VERSION
How a Slime Mold Came to the Aid of Alzheimer's
In an ancient Persian fable, three princes
from the kingdom of Serendip go out into the world to gain experience.
During their adventures, they find they have a gift for making unexpected
Like those fabled princes, UGA cell biologist Marcus Fechheimer and his
research team have discovered they too have a gift for serendipity.
In the course of trying to understand how proteins “know” where
to go in a cell, the researchers unexpectedly stumbled upon an unusual
cellular structure normally associated with Alzheimer’s and other
“I didn’t think we were working
on anything that had to do with Alzheimer’s disease,” said
Fechheimer, who uses a slime mold as his lab’s version of a “guinea
“We didn’t expect to find a structure in a slime mold that
is present in increased amounts in people with Alzheimer’s — particularly
present in the brain’s major site of learning and memory. That’s
where these things accumulate,” he said.
Fechheimer’s team not only chanced upon this unusual structure — called
a Hirano body — in a slime mold but also figured out how to force
cells to produce them on command in the laboratory. Up till now, these
structures could only be studied in brain tissue of people who had died.
Because of this discovery, scientists will be able to study Hirano bodies
in living cells for the first time and unravel the mysteries of this little-understood
Though Hirano bodies are common in the brains of people diagnosed with
dementia, their role in disease, if any, is unclear.
“We don’t know if a Hirano body is good or bad or why it’s
there or how it forms,” said Ruth Furukawa, a UGA research scientist
who co-directs the study.
Proteins run amuck
What causes neurodegenerative diseases like Alzheimer’s
is still largely unknown, but something destroys nerve cells in the brain
over a period of time as victims gradually lose their minds.
In the hunt for cause and cure, scientists have focused on various abnormal
protein deposits that mar diseased brains. Deposits called plaques and
tangles have captured the most attention. Hirano bodies, while not at the
forefront of Alzheimer’s research, are another type of protein deposit
associated with the disease.
“Hirano bodies are certainly more prevalent in brains from patients
who are suffering from dementias, probably any type,” said James
Bamburg, one of Fechheimer’s collaborators and a professor of biochemistry
and molecular biology at Colorado State University. “Hirano bodies
also occur in brains of individuals with normal cognitive function but
usually increase in number with age.”
Nearly four decades have passed since Asao Hirano, an eminent neuropathologist
at Montefiore Medical Center in New York, first discovered the peculiar
deposit in the brain’s memory center. Since then Hirano bodies have
been reported in the brains of people with neurodegenerative diseases,
as well as diabetes, stroke and alcoholism.
“Making a Hirano body may be a cellular mechanism for dealing with
run-amuck proteins,” said Furukawa, who manages the day-to-day operation
of the lab. “That’s just a hypothesis.”
Run-amuck proteins certainly seem to play some role in all the diseases
where Hirano bodies are found.
“Perhaps Hirano bodies do nothing; perhaps they’re part of
cell death; or perhaps they are adaptations to stress that are good for
said. “Because they’re seen in so many diseases, it’s
worth finding out.”
After more than 20 years probing basic questions in cell biology, Fechheimer’s
team is well positioned to explore the role of Hirano bodies in cells and
in human disease.
The path to hirano bodies
But how did a cell biologist studying cell movement and structure — in
a lowly slime mold no less — end up investigating
something that may have a role in degeneration of the human brain? It seems
like a stretch at first.
Basic but complex questions in cell biology have piqued Fechheimer’s
curiosity and driven his research program for more than two decades: How
do cells move? What gives them shape? How do they eat?
The key to such riddles resides in a fibrous network inside cells, a kind
of internal micro-scaffolding called the cytoskeleton. Besides acting like
the “bones” of a cell, the cytoskeleton is an intracellular
highway system, where specialized proteins scoot along the roadways toting
organelles and other materials to the places they need to be.
“When we look at something that seems very obvious and beautiful
like a crawling amoeba, it’s almost beguiling in its simplicity,” Fechheimer
said. “But then you think about all the different molecular interactions
and changes just in the actin when a cell is crawling forward. There are
a lot of different things going on in different places. Figuring out all
those dynamics is very complicated and very exciting. And we have great
tools today to do it.”
To uncover the secrets of cell structure and movement Fechheimer’s
team probed the inner workings of molecules that make up the cytoskeleton.
The “roadways” consist of filaments made of three distinct
proteins — one of which is actin — along with helper proteins
that either anchor or bundle the filaments.
Actin doesn’t work alone. Among its helper molecules is a family
of proteins that include one called the 34 kDa actin bundling protein.
As its name implies, the 34 kDa protein packages actin filaments into bundles.
Actin bundling proteins play important roles in a variety of processes
in the body.
“These actin bundles are ubiquitous,” Fechheimer said. For
example, they have a role in hearing.
“The pressure wave that comes into your ear actually deflects actin
bundles that are arranged like a staircase in the sensory hair cells and
electrical signal gets sent to the brain,” he said.
During the past two decades, Fechheimer’s team has systematically
answered many questions about the 34 kDa protein. They pinpointed where
it is found in cells and what controls its ability to stick to actin. They’ve
uncovered the protein’s structure. Along the way, they’ve looked
at how it works by chopping the protein into pieces and testing how different
snippets bind to actin.
To fine-tune their understanding of what the bundling protein does and
how it works, they have altered the gene for the 34 kDa protein in small
ways and inserted the altered version back into cells to see what happens.
That’s what Andrew Maselli was doing when he discovered something
Serendipity and beyond
Unlikely as it might have seemed, the bundling protein proved to be the
key to the team’s discovery of Hirano bodies in the slime mold. Hirano
bodies, it turns out, are partially made of actin; a piece of the actin
bundling protein triggers cells to make Hirano bodies.
“I was studying the 34 kDa actin bundling protein and I wanted to
know how it got where it needed to go in the cell to form the structures
and eating,” said Maselli, a former UGA doctoral student who is now
an assistant professor at Chicago State University.
Other scientists already had demonstrated the bundling protein’s
role in making structures that enable cell movement and feeding, Maselli
said. But no one had looked at how the protein “knew” to go
help form those structures.
Figuring out how a protein like this one works is like figuring out how
a clock works: Remove a piece from the clock, tinker with it a bit, put
it back in and see what happens.
Maselli took the gene for the bundling protein, removed bits from it, put
it back in the slime mold and watched to see what happened. He suspected
that calcium helped control the protein’s travels in the cell so
he removed the bits that interacted with calcium.
“These structures formed that are very striking,” Maselli said. “It
took a while before I was convinced that what I was seeing was interesting
biologically and not just some artifact.”
In the slime mold cells with the altered bundling protein, Maselli and
colleagues observed large, almond-shaped areas packed with parallel filaments.
Nothing like this had ever been seen in a slime mold.
Maselli credits Fechheimer with recognizing that these strange bodies resembled
the Hirano bodies previously described in brain tissue. The team set out
to confirm Fechheimer’s hunch.
When the researchers examined the mysterious structures with an electron
microscope, they discovered a match with Hirano bodies’ characteristics.
Filament width and spacing, the pattern that filaments formed and the overall
shape of the body all checked out, said doctoral student Rich Davis.
Next, the researchers used antibodies that “recognize” specific
proteins and showed that the alleged Hirano bodies were made of actin and
a handful of other proteins. Finally, Davis inserted the altered gene into
mammalian nerve cells and fibroblasts growing in the lab, and the same
structure formed in them.
Fechheimer’s team was convinced that what they were seeing in the
slime mold, and now in cultured mammalian cells, were indeed Hirano bodies.
The scientists now had a way to investigate how Hirano bodies form, what
they do and what their fate is: Insert the altered gene in a cell, and “presto” you’ve
got Hirano bodies.
“Because it’s novel and a model system, you ask some very basic
said. “It’s hard to get to the more subtle questions until
you figure out some basic biology.”
And basic questions abound: Do cells grow normally if they have Hirano
bodies? What are Hirano bodies made of? What is their purpose?
So far the UGA team has discovered that slime mold cells with Hirano bodies
grow normally or a bit more slowly but complete their life cycle.
“Further, mammalian cells with Hirano bodies also grow normally in
Hirano bodies are made of several hundred proteins; only a half dozen or
so have been identified. But which ones are required to make the deposits?
Graduate and undergraduate students are trying to find out, Furukawa said.
“Even though Hirano bodies look like they are mainly made of actin,
there are a lot of other things in there as well,” said doctoral
student Paul Griffin. “People speculate there might be growth factors
in there, transcription factors, all kinds of things. That’s what
like to elucidate.”
But the big question is: What do these things do? Answering that question
may finally explain the link to Alzheimer’s and other brain disorders.
“The idea that Hirano bodies are simply a manifestation of cell death
is not being born out by our studies,” Fechheimer said.
Davis exposed cells that make Hirano bodies to oxidative stress to see
whether they live or die. Early evidence indicates that Hirano bodies actually
may have a protective function — bundling up damaged proteins and
spitting them out of the cell. Future studies by graduate student Sang
Deuk Ha will further probe the protective nature of Hirano bodies in mammalian
“We can make the Hirano bodies in Dicytostelium, in fibroblasts,
in epithelial cells, in nerve cells in culture,” Fechheimer said. “So
far the answer seems to be that Hirano bodies don’t hurt these cells
and perhaps they are protective.”
With one interesting twist.
When Davis introduced the altered bundling protein gene into HeLa cells — cultured
human cervical cancer cells — the cells died. In fact, they underwent
apoptosis, the scientific name for programmed cell death. Intriguingly,
HeLa cells do not appear to form Hirano bodies, unlike the other cell
types examined to date.
Fechheimer speculates that the modified HeLa cells undergo apoptosis
due to their failure to form Hirano bodies, further evidence to support
idea that Hirano bodies may play a protective role. Now Davis, Ha and
undergraduate Dan Del Portal are investigating the relationship between
and this type of cell death.
Still, it could be years before the link between Hirano bodies and neurodegenerative
diseases is better understood.
“It’s really about asking the question and solving the problem in
such a way that you get a clear answer,” Furukawa said. “When
you work in biology, you can ask every question you can think of but
that doesn’t mean you can think of a way to get an answer, and
some straightforward answer, not some murky answer.”
Future studies in the slime mold and other kinds of cells will uncover
what Hirano bodies are made of, how they form and whether they are essential
for certain cell processes. Knowing how Hirano bodies behave in cell
culture is not enough. For that reason, Fechheimer’s group also
plans to study them in entire organisms such as transgenic fish and mice.
“Our findings grew out of research funded by the National Science Foundation,” said
Fechheimer, who also received support from the Alzheimer’s Association
once the link to neurodegenerative disease was established. “That’s
why NSF is very excited by this connection to something that sounded
like brain disease. To them it was a wonderful example why you never
want to forget about investing in basic research.”
You never know what serendipitous discovery might be around the next
more information, contact Marcus Fechheimer at email@example.com oraccess www.uga.edu/cellbio/fechheimer.html
Kathleen Cason is associate director of Research Communications
at the University
What Goes Wrong
By the time British author Iris Murdoch felt that she was “sailing
into the darkness,” Alzheimer’s disease had long been at work
on her brain.
At one time, Murdoch could compose books — in their entirety — in
her mind. But in a handful of years, the disease transformed her brilliant
intellect to that of “a very nice 3 year old,” according to
her husband, John Bayley.
Her dark descent, captured in the recent movie Iris based on Bayley’s
books, illustrates the plight of some 4.5 million Americans, a number expected
to more than triple by 2050.
What goes so terribly wrong in the brain of an Alzheimer’s patient?
This much we know: In Alzheimer’s disease, lesions — called
tangles and plaques — pepper the brain’s memory center like
buckshot. The tangles clog nerve cells with gummed up cytoskeletal proteins.
Plaques — accumulations of a toxic snippet of a protein — gunk
up the spaces between cells. And brain tissue gradually disappears along
with the victim’s memories.
“You’re looking at a disease that has been progressing for
30 years,” said
Sangram Sisodia, director of the Center for Molecular Neurobiology at the
University of Chicago and a leading Alzheimer’s researcher. “The
plaques and tangles are the tombstones of the disease.”
The search for an exact cause has led scientists to suspect that a toxic byproduct
of a cell protein damages and kills nerve cells in the process of forming plaques.
“Genetics points me in the direction of a molecule called a-beta and a-beta
said. The UGA alumnus earned his doctorate under the direction of Gordhan Patel,
who is now UGA’s Vice President for Research.
Plaques form when a normal cell protein called APP — or amyloid precursor
protein — gets cut by enzymes in the wrong spot, releasing a toxic fragment
called a-beta peptide. The plaques themselves are not thought to kill brain cells;
scientists suspect that a wayward form of the a-beta peptide is the culprit.
“The a-beta peptide not only accumulates in plaques but along the way it
form these little fibrils that will be free-floating in the brain,” said
Rudolph E. Tanzi, professor of neurology at Harvard Medical School and director
of the genetics and aging research unit at Massachusetts General Hospital. “The
fibrils can interact with neurons and cause problems, from blocking neural transmission
to actually killing nerve cells.”
Sisodia, Tanzi and many other researchers have hunted for genetic evidence by
turning to families where Alzheimer’s disease strikes early — in
the third or fourth decade of life, sometimes even earlier.
“The pathology in individuals who inherit these genes for early-onset Alzheimer’s
disease and the clinical symptoms are almost indistinguishable — with some
minor variations — from somebody who gets the disease in the late onset
form,” Sisodia said.
So far, the genetic clues support the notion that a-beta peptide production in
the brain is the probable cause of Alzheimer’s disease.
“The pathological cascade inside the cell revolves around the life cycle
a-beta peptide,” said Tanzi, co-author of Decoding Darkness: The Search
for the Genetic Causes of Alzheimer’s Disease.
The disease occurs when a person has defective genes that either make too much
APP or produce enzymes that cut APP in the wrong place, releasing the “bad” a-beta.
But a-beta production alone won’t cause the plaques to form; a-beta has
to clump together into fibrils to be toxic to nerve cells. If enzymes chop up
a-beta or if a-beta is shuttled into the blood where it can be disposed of, clumping
doesn’t occur, Tanzi said.
“If too much a-beta is made at once and the machinery for clearing it or
it can’t keep up, it’s going to form fibrils more readily,” Tanzi
said. “They’re going to cause neurotoxicity and eventually it’s
all going to manifest itself in senile plaques.”
Scientists still have much to learn about this bewildering disease that kills
the mind long before the body dies. Several UGA researchers are contributing
to understanding Alzheimer’s disease in a variety of studies. They include
• Cell biologist Marcus
Fechheimer and his research team developed a system to
investigate abnormal cell structures called Hirano bodies and what their role
may be in Alzheimer’s and other neurodegenerative diseases.
Schmidt, assistant professor of biochemistry and molecular biology, studies several
enzymes in yeast that bear similarities to enzymes thought to have roles in Alzheimer’s
and other diseases. One of those enzymes is similar to insulysin — or IDE — which
may remove the a-beta peptide from the brain.
• Alan Przybyla’s biochemistry and molecular biology lab has
developed a method to produce a recombinant form of the a-beta peptide. He helped
start-up company, rPeptide, that provides researchers around the world with molecules
involved in Alzheimer’s, Parkinson’s and other diseases.
William Kisaalita, associate professor of biological engineering, is developing
cell-based tests, or biosensors, to screen drugs for Alzheimer’s disease.
• Alvin Terry, associate professor of pharmacy, studies the long-term
effects of medication on the brain, particularly medications commonly used to
with diseases that affect memory, like Alzheimer’s disease and schizophrenia.
Disease: A Checklist of Symptoms
1. Memory loss. Forgetting names, appointments and telephone numbers.
2. Difficulty performing familiar tasks. Unable to prepare a meal, use
household appliances or participate in a lifelong hobby.
3. Problems with language. Trouble finding the right word.
4. Disorientation to time and place. Become lost on their own street.
5. Poor or decreased judgment. Wears inappropriate clothes for the weather.
6. Problems with abstract thinking. Balancing a checkbook is difficult.
7. Misplacing things. Puts an iron in the freezer or a wristwatch in the
8. Changes in mood or behavior. Rapid mood swings.
9. Personality changes. May become extremely confused, suspicious, fearful
or dependent on a family member.
10. Loss of initiative. Becomes passive, sleeps more, not interested in