June 29, 2009

A Broader Role for Amyloids

Electron micrograph of a cell packed with round granules A cell from the pituitary gland stores the hormones it produces in granules (green). Wellcome Images.

Amyloids are best known for their role in diseases such as Alzheimer’s. A new study finds that amyloids may also have a normal biological function.

Alzheimer’s and other related diseases are marked by clumps of protein fibers that accumulate around nerve cells in the brain. These dense plaques are made of proteins that are normally found in the body but have misfolded to form amyloids. Amyloid can also cause problems beyond the brain. For example, they can form waxy protein deposits that stiffen the heart, limiting its pumping ability and leading to fatal heart stoppage.

Amyloids are actually defined by their structure, not the specific proteins that form them. They are made of highly organized protein arrangements called β-sheets that stack perpendicularly along the axis of the amyloid fiber.

A research team led by Dr. Roland Riek of the Salk Institute for Biological Studies noted that structures called secretory granules also have a highly ordered organization. Secretory granules allow cells that secrete hormones and other molecules to store those molecules in a highly concentrated form. With funding from NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the researchers explored whether protein hormones could form amyloids.

The scientists exposed 42 hormones in the lab to conditions similar to that in the Golgi complex, the part of the cell where secretory granules form. In the June 18, 2009, online edition of Science, they reported that, at first, 10 of the hormones formed amyloids. However, when they added a type of molecule known to be involved in forming both secretory granules and amyloids, 31 of the hormones formed amyloids.

Amyloids are notoriously stable, but secretory granules must release their molecular contents in order to work properly. The researchers thus exposed the amyloids they’d made to the conditions they would experience upon being secreted. All the hormone amyloids appeared to release their component hormones under these conditions. Further tests revealed the hormones to be functional.

Since amyloids are thought to be toxic to neuronal cells, the researchers tested whether the ones they’d created were toxic to a neuronal cell line in the laboratory. Some proved moderately toxic. But the scientists noted that their actual toxicity in the body could be substantially lower, because they’re stored inside granules and encapsulated by a membrane.

The researchers next examined secretory granules purified from a pituitary tumor cell line and from rat pituitary tissue. Both types appeared to be composed of amyloids. Amyloids also appeared to be present in secretory granules in mouse pituitary tissue.

These experiments provide evidence that secretory granules contain amyloids, and that amyloids help the body store and release hormones. Previous research has found that amyloids also play a role in forming melanin, which helps protect the skin from sun damage. Together, these studies suggest that amyloids may play normal roles throughout the body. It may not be amyloids themselves that cause disease, but rather conditions that lead too much amyloid to form in the wrong places. Future research will be needed to better understand the role of these molecular structures in disease.

—by Harrison Wein, Ph.D.

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