Article Review (2007) - Structural analyses of fibrinogen amyloid fibrils

Today's article under review actually covers two articles with essentially the same title and the same authors. The 2007 article published in the journal Amyloid is actually a slightly longer and more detailed version of a paper presented at the XIth International Symposium on Amyloidosis in November of 2006. I have previously reviewed three papers from the 2006 symposium that were published in the book XIth International Symposium on Amyloidosis, edited by Drs. Skinner, Berk, Connors and Seldin. The first of those reviews was in the November 25, 2013 post.

Since these two articles cover the same material, I will give the information for both articles first, and then review the second one. In contrast to the previous article review, which showed how fibrinogen amyloidosis is different than other types of amyloidosis, these articles show how fibrinogen amyloidosis is similar to the other types, including AL.

Title: Structural Analyses of Fibrinogen A Alpha-Chain Amyloid Fibrils (1)

Authors: L. C. Serpell, M. D. Benson, J. J. Liepneiks, and P. E. Fraser (University of Sussex, Brighton, UK; Indiana University School of Medicine, Indianaposis, IN, USA; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA; Centre for Research into Neurodegenerative Diseases, Toronto, Ontario, Canada)

Book: XIth International Symposium on Amyloidosis (2007)

Abstract: None



Title: Structural analyses of fibrinogen amyloid fibrils (2)

Authors: L. C. Serpell, M. D. Benson, J. J. Liepneiks, and P. E. Fraser (University of Sussex, Brighton, UK; Indiana University School of Medicine, Indianaposis, IN, USA; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA; Centre for Research into Neurodegenerative Diseases, Toronto, Ontario, Canada)

Journal: Amyloid (2007)

Abstract: 

Hereditary fibrinogen amyloidosis is characterized by deposition of amyloid fibrils in renal glomeruli. The subunit protein of the amyloid fibrils is a proteolytic fragment of the fibrinogen Aα-chain. To investigate the structure of fibrinogen amyloid, fibrils were extracted from the tissues of a patient and studied by X-ray fiber diffraction and electron microscopy. We have carried out a full structural characterization of amyloid fibrils taken from disease tissue. These studies revealed that ex vivo fibrinogen amyloid fibrils have a cross-β structure similar to other chemical types of amyloid fibrils.

As I mentioned at the end of the previous post, these articles have a lot of technical information. The topic is the amyloid fibrils themselves, specifically their molecular structure. Most of it is beyond my understanding, and although it does not have any direct impact currently in terms of diagnosis or treatment, it may be important as amyloidosis treatments are developed in the future.

If you read much about amyloidosis in general, you will likely encounter the terms "beta sheets," "beta-pleated sheets," or "cross-beta structure." (Instead of writing out the word "beta", the symbol "β" will often be used, as it is in the abstract above.) In reviewing these articles today we learn what a beta sheet is, and whether or not fibrinogen amyloidosis forms beta sheets like other forms of amyloidosis. So, what is a beta sheet? Quoting from Wikipedia, beta sheet is the second form of regular secondary structure in proteins, and it is less common than the alpha helix. Huh? Let's see if I can explain that a little better, given my ten minutes of Wikipedia research. (For a more thorough explanation than the following, see the Wikipedia articles on "biomolecular structure" and "beta sheet.")

Beta sheet is one of two standard ways of describing the general three-dimensional form of a protein. The other one is alpha helix. These are not intended to be accurate three-dimensional models of the protein molecules, but instead have to do with how they bond together. Just think of alpha helix as a spiral, and beta sheet as a curved sheet or a ribbon, and that gets you close enough for our purposes.

Amyloidosis is often referred to as a protein misfolding disorder. In over-simplified terms, the shape of a protein, or how it is folded, is very critical to ensure it does its job in the body, whatever that may be. When a protein is misfolded, sometimes the body just gets rid of it. But at other times, such as with amyloidosis, these misfolded proteins build up and form deposits in various places in the body. In the case of AL amyloidosis, it has been known for some time that the misfolded proteins form beta sheets. The purpose of this article was to determine if amyloid deposits due to fibrinogen amyloidosis also form beta sheets.

In order to analyze the structure of fibrinogen amyloid material they isolated some tissue from a spleen that was removed from a fibrinogen amyloidosis patient. This patient was the propositus of one of the kindreds described in the first report of the Glu526Val mutation, which I reviewed in the March 20, 2013 blog post. The current article states this patient had a kidney transplant that failed, so he was on dialysis for several years and eventually developed an enlarged spleen that had to be removed.

The article goes into great detail on the laboratory procedures that were used to isolate and then analyze the amyloid fibrils from the spleen. They did stain some amyloid fibrils with Congo red at one point, to confirm they were indeed amyloid. And when viewed under an electron microscope, the fibrils were long, straight and unbranching, which resembles amyloid fibrils due to other types of amyloidosis. Using a technique called X-ray diffraction they were able to determine that the amyloid fibrils formed a cross-beta structure, which is also common to other types of amyloidosis. The article then goes into some more detail on the actual dimensions and angles of the beta sheet, and it states that the amyloid fibrils are composed of a fragment of the fibrinogen A alpha chain that is approximately 80 amino acids long. (A complete fibrinogen A alpha chain is composed of 610 amino acids.)

So this article is definitely on the technical side and does not give us any new information regarding the diagnosis or treatment of fibrinogen amyloidosis. But perhaps this information will some day be useful in the development of drugs that can either prevent the amyloid fibrils from initially forming, or cause the amyloid deposits to be dissolved.

In the next article up for review, we have a report of fibrinogen amyloidosis from yet another country in Europe.

=====

Citations:

(1) Skinner M, Berk JL, Connors LH, Seldin DC. XIth International Symposium on Amyloidosis: Taylor & Francis; 2010.

(2) Serpell LC, Benson M, Liepnieks JJ, Fraser PE. Structural analyses of fibrinogen amyloid fibrils. Amyloid. 2007;14(3):199-203.