Vol 5. Issue 37 / December 5, 2005

"Unprecedented" Functional Amyloid Found to Play Beneficial Role In Human Cells

A group of scientists at The Scripps Research Institute have shown that the amyloid protein structure, which has been linked to neurodegeneration in diseases including Alzheimer's, Parkinson's, and Huntington's, carries out an important functional role in human physiology. The discovery raises the possibility that current research into curtailing amylolid formation to treat these diseases might ultimately do as much harm as good. The discovery of functional amyloid in a range of organisms, which now includes humans, suggests that it was present early in evolution, and was retained for a fundamental role in normal mammalian cell physiology.

The new study, which will be published online November 29, 2005 in the journal PLoS Biology was jointly overseen by Scripps Research investigators Jeffery W. Kelly and William E. Balch. Kelly is the Lita Annenberg Hazen Professor of Chemistry, a member of The Skaggs Institute for Chemical Biology, and vice president of academic affairs at The Scripps Research Institute. Balch is a Professor of Cell Biology and a member of the Institute for Child and Neglected Diseases at Scripps Research. 

"The fact that we have found a structure in humans that is usually only associated with pathology is a critical new finding," Kelly said. "Numerous pharmaceutical and biotechnology companies have development programs to inhibit amyloid formation to help treat Alzheimer's and related diseases. It's now clear from our results that if non-selective amyloid inhibitors got into cells, they would likely interfere with melanogenesis, which protects against a wide range of internal and external injury."

Other members of the research team include Douglas M. Fowler of Kellogg School of Science and Technology; Atanas V. Koulov and Christelle Alory-Jost of the Scripps Research Department of Cell Biology and the Institute for Childhood and Neglected Diseases; and Michael S. Marks of the Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.

Amyloid is an insoluble, fibrous protein structure formed by the interaction of identical protein molecules having an extended shape. The process of amyloid fibril (sometimes called amyloid plaque) formation is most commonly associated with variety of neurodegenerative diseases. However, Kelly and his colleagues showed that these same fibrils are abundant in melanin-producing cells where they help synthesize the pigment melanin. Melanin is one of the body's chemical defenses against pathogens, toxic small molecules, and protects the skin and eyes from the ultraviolet rays of the sun. It is produced in parts of specialized cells of the skin and eyes called melanosomes. 

Kelly and his colleagues discovered that melanocytes were filled with a specific amyloid plaque produced by the Pmel17 protein. The Pmel17 amyloid fibrils perform a complex function in human cells, orchestrating the polymerization (forming large molecules from smaller ones) of a potentially toxic metabolite into melanin, likely influencing its structure and reducing toxicity during melanization.

Until this study, nonpathogenic amyloid had not been detected in mammals and its very existence was unexpected because of the toxicity generally associated with its formation. This new discovery clearly challenges the conventional view that amyloid in mammals is always cytotoxic. The study was conducted using both in vitro and ex vivo experiments.

"Our discovery clearly demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans," Kelly said. "We found that while functional and pathological amyloids share similar structural features, there were distinct differences in how they form. The discovery of native Pmel17 amyloid in mammals strongly suggests that this amyloid may be an ancient, evolutionarily protein structure that contributes to normal cell and tissue physiology. We suspect that the reason amyloid has not been identified before in mammals is its insoluble non-crystalline form."

Kelly and his colleagues concluded that the amyloid structure may have been selected multiple times during evolution for a variety of functions, once again contrasting with the current view that there was evolutionary pressure against retention of the amyloid fold. The rapidity of recombinant Pmel17 fibrilization in a test tube was consistent with an evolutionary process optimized for functionality and to avoid the toxicity of pathological amyloidogenesis.

While functional amyloidogenesis exhibits some similarities to pathogenic amyloid formation, several key differences in packaging and assembly appear to enable the utility of amyloid as a major intracellular structure for normal cell function. The study went on to suggest that this newly discovered functional amyloid be renamed amyloidin, with the clear expectation that more of these functional structures will be discovered.

Further study of the functional amyloidogenesis pathway is likely to provide critical insights into the pathological basis for neurological disorders like Alzheimer's disease, where the difference between normal and pathological amyloid synthesis is currently not recognized. This information may well point towards the discovery of amyloid in other important functional roles as well.

This research was funded by the U.S. National Institutes of Health, The Skaggs Institute of Chemical Biology at Scripps Research, and the Lita Annenberg Hazen Foundation.


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"The fact that we have found a structure in humans that is usually only associated with pathology is a critical new finding."

—Jeffery Kelly