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First live studies of important cell structures may shed light on Alzheimer's, other diseases

University of Georgia

A just-published study describes for the first time a method of culturing important but poorly understood cell structures called Hirano bodies. The report by cellular biologists at the University of Georgia could shed light on numerous diseases in which Hirano bodies may play some role - including Alzheimer's disease, Lou Gehrig's Disease and cancer.

The research was just published in the Journal of Cell Science and was funded by the National Science Foundation and the Alzheimer's Association.

Hirano bodies - named for their discoverer - have been known for several decades, and their presence in autopsy tissue of Alzheimer's patients has led to speculation that they may play a role in disease processes. Studying Hirano bodies, however, has been extremely difficult because they have been resistant to culturing in the laboratory.

The new study, led by UGA cellular biologist Marcus Fechheimer, reports a novel way to create Hirano bodies in the lab, giving scientists their first tool in understanding how the bodies may aid - or hinder - the progress of disease.

"I am honored that we have been able to do the basic research that has led us to this point," said Fechheimer. "We now have the opportunity to proceed to work of medical significance, and that is very exciting."

Other authors on the paper from Fechheimer's lab are graduate students Rich Davis and Andrew Maselli and research scientist Ruth Furukawa.

Scientists have for three decades found Hirano bodies in the post-mortem examination of brain tissue from patients with neurodegenerative diseases, diabetes, alcoholism and cancer. Hirano bodies are composed of filaments of actin, actin-binding proteins and other as-yet-unknown components.

One example of how little is known about these bodies is that a search on a popular Web browser that examines three billion Web pages found less than 200 references to them - and most of these references are to autopsy findings. The Fechheimer paper reports the first method of reproducing Hirano bodies in the lab - a key that could open doors to new studies.

Just what Hirano bodies do remains murky at best. They may change cells to make them more vulnerable to disease, but it's just as likely at this point that they help battle disease - no one knows. That's why the new results are exciting and offer a key tool for investigations of these structures.

The team used an unlikely candidate for a model system for neurodegenerative disease: the slime mold Dictyostelium. The discovery of Hirano bodies in Dictyostelium was an accidental offshoot of basic cell biology research that Fechheimer and his students pursued for more than a decade.

"The formation of Hirano bodies in Dictyostelium came about by serendipity," said Fechheimer. "I was at a meeting of the American Society of Cell Biology, when Dr. James Bamburg of Colorado State saw one of my photos of a Dictyostelium strain we had engineered and told me that parts of the cell looked just like Hirano bodies. That made me really sit up and take notice."

That meeting led Fechheimer on a journey to determine whether the structures were indeed Hirano bodies and to find a mammalian system to which he could compare them. The new paper reports success in the former research and the successful use of mouse cells for the latter. Together, the paper makes a strong case that Hirano bodies can be reproduced in laboratory model systems.

Dictyostelium is, in many ways, an ideal though offbeat candidate for study of Hirano bodies. It has long been a model system for studies of cell structure and movement. Fechheimer found that the slime mold could be induced to form Hirano bodies in the presence of altered forms of an actin bundling protein called 34-kDa.

The research team found at least five points of similarity between Dictyostelium Hirano bodies and those found from human autopsy samples, including an elliptical cross-section, the juxtaposition of ordered and disordered regions, paracrystalline filaments arranged in a broad range of spacings and the presence of actin and cofilin.

But how are Hirano bodies formed and what do they do in cells? The paper in the Journal of Cell Science proposes that the bodies are induced by the expression of a modified form of an actin-cross-linking protein called CT. Low levels of the CT protein in Dictyostelium, it turns out, induce the formation of Hirano bodies, and a similar expression of this CT fragment induces formation of the bodies in mouse cells.

"These results show that formation of Hirano bodies is restricted neither to mammalian cells nor to nerve cells," wrote Fechheimer. "Rather, the formation of Hirano bodies appears to be a general response to or consequence of aberrant function of the actin cytoskeleton."

Until now, Hirano bodies have been found by autopsy most often in the hippocampus region of the brain, though the bodies are not restricted to neurons. Still, the bodies appear to have some association with a wide range of diseases, including those mentioned earlier, along with ataxic Creutzfeldt-Jakob disease and Pick's disease (both neurodegenerative disorders) and diabetes.

The presence of Hirano bodies in association with all these diseases has led scientists to speculate that they have some role in neurological deterioration - especially in diseases such as Alzheimer's. Fechheimer and his colleagues, however, argue that their results support a broader interpretation. They propose that a range of conditions may generate signals that cause the rearrangement of the actin cytoskeleton and induce the formation of Hirano bodies. If this is true, then the study of Hirano bodies takes on new and stronger importance because it may be possible to determine whether the bodies are actually involved with diseases.

So far, that's been a major headache for scientists: No one knows whether these bodies are doing good things for cells or bad ones. Some researchers had speculated that the bodies played a role in apoptosis or so-called "programmed cell death," in which cells signal for their own demise, sometimes for the good of the entire organism but often not. Fechheimer's work shows that Hirano bodies, however, are not necessarily linked to a stage in cell death.

The new ability to create Hirano bodies in the lab will, however, allow researchers to explore their mechanisms with greater understanding than ever before.

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