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A new molecular culprit for type II diabetes, Alzheimer’s and Parkinson’s

22.10.2003


Therapies for Alzheimer’s, Parkinson’s and type II diabetes should be directed toward a new molecular culprit — the precursor to the clumps of abnormal proteins that have garnered attention for the last century.



Israeli scientists say they have solid evidence that the precursor molecules — called protofibrils — are the problem molecules in type II diabetes, and their results support a similar mechanism for Alzheimer’s and Parkinson’s. Further, they say that the current focus on breaking up the abnormal clumps of protein — called fibrils — may in fact be doing more harm than good.

The report appeared in the Sept. 23 edition of Biochemistry, a peer-reviewed journal of the American Chemical Society, the world’s largest scientific society.


Proteins are the chemical workhorses of the body. These long chains of amino acids fold into myriad forms, but they must assume the right three-dimensional structure to function properly. Misfolded proteins are the basis of a number of seemingly unconnected diseases, including age-related diseases like type II diabetes, Alzheimer’s and Parkinson’s, as well as "mad cow" (BSE) and other prion diseases.

Despite many years of investigation, the actual mechanism of misfolding has eluded researchers, leaving them without the understanding necessary to develop effective treatments or even properly diagnose the diseases.

The most popular theory has revolved around long clumps of misfolded proteins known as amyloid fibrils that kill cells in patients. Therapeutic efforts have focused on breaking up these deposits. In Alzheimer’s they are called amyloid plaques; in Parkinson’s they are called Lewy bodies; in type II diabetes they are called islet amyloid deposits and occur in the "islets of Langerhans," the area of the pancreas where insulin is produced and regulated.

"Type II diabetes is one of the most common amyloid-related diseases," says Ehud Gazit, Ph.D., a researcher at Tel Aviv University in Israel and lead author of the study. "The Centers for Disease Control and Prevention in Atlanta estimate that more than 18 percent of American adults older than age 65 have diabetes, almost entirely of type II." As the life expectancy of people around the world continues to increase, this and other age-related diseases will become an even greater public health concern, he says.

Scientists have previously suggested that mature fibrils of the amyloid polypeptide protein — the key component of the islet deposits — are toxic to cells in the pancreas that produce insulin, attacking through tiny holes in the cell membrane. Gazit and his colleagues, graduate student Yair Porat and Sofiya Kolusheva and Raz Jelinek from Ben Gurion University, studied the interactions between the protein and cell membrane. They discovered that smaller structures formed prior to the mature fibrils, called protofibrils, are more likely to get through the membrane, and may therefore be the more toxic species.

In the past few years, other scientists have noticed the effects of protofibrils while studying Alzheimer’s and Parkinson’s, but the notion that they may be the main culprits is fairly new. Earlier this summer in another Biochemistry paper, Peter Lansbury of Harvard University suggested a possible therapeutic strategy for Parkinson’s based on stopping the formation of protofibrils.

"A very interesting point is the striking similarity between these assemblies and the structures observed in the cases of Alzehimer’s disease and Parkinson’s disease," Gazit says. The new study offers solid experimental evidence of the phenomenon in type II diabetes, and demonstrates a common thread among the three diseases.

The majority of research continues to focus on mature fibrils, but this could prove to be dangerous if the new protofibril mechanism is correct, according to Gazit. Breaking up the large amyloid deposits may actually increase the number of protofibrils, thus increasing the level of toxicity to the body.

Gazit’s new research on protofibrils is still in the early stages, but it suggests the need for a shift in focus from breaking up mature fibril deposits to inhibiting the earlier stage of protofibril formation. His group has designed several potential inhibitor molecules and they are currently testing their potency.

Michael Bernstein | EurekAlert!
Further information:
http://www.acs.org/

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