Amyloid science
Amyloid fibrils are made from normally-soluble proteins that stick together to form insoluble aggregates. They have a distinctive appearance under an electron microscope—long, straightish fibrils around 10 nm (a hundred-millionth of a meter, or about four ten-millionths of an inch) in diameter. Around thirty proteins are known to form amyloid and cause disease, but many more—perhaps most proteins—can be made to aggregate in vitro. Amyloid formation is a fundamental property of proteins’ polypeptide backbone.
Although the sequences and structures of the precursor proteins differ, the underlying structure of the fibrils is similar. The spine of an amyloid fibril has a cross-beta secondary structure—beta strands from many individual molecules aligning perpendicular to the fibril axis, with intermolecular hydrogen bonds parallel to the fibril axis. Most amyloid fibrils have short sections of parallel, in-register, cross-beta sheets connected by turns and loops. In the last few years we have gone from determining the structures of minimal, artificial amyloid fibrils to much more complex structures extracted from brains—a revolution driven mainly by amazing technical advances.
Not all amyloids are harmful. There are several functional proteins that use amyloid-like structures to form large assemblies or fibrils. The best-known example is silk. However, amyloid is mostly thought of as a pathological aggregate, the hallmark of a range of diseases. Amyloid deposition is associated with cell death and organ dysfunction, but it’s not clear why or how this happens. The original definition of amyloid has blurred over the years as more examples have been discovered of protein aggregates associated with disease, or with function. The latest hot topic is “liquid-liquid phase transitions” – transient condensation of proteins within cells that seem to be involved in a huge range of functions.
So why don’t more proteins form amyloid? Most proteins need to fold into a specific shape its “native state” in order to function. The ability to fold correctly has been strongly selected for, so that the vast majority of proteins maintain their correct shape and function. However, rare mutations or environmental challenges can interfere with proteins’ ability to fold, which can allow them to occasionally form non-native structures. Amyloid fibrils are stable and insoluble, so they accumulate in the body. Over time, this can lead to disease.
Amyloid diseases come in two main forms. Systemic amyloidosis is caused by a protein secreted from one organ that forms amyloid deposits elsewhere in the body. This is the class of diseases that the Amyloidosis Center was founded to treat. These diseases can sometimes be treated by blocking the production or misfolding of the precursor protein. The other type of amyloid disease is organ-localized — proteins deposit within the organ or cell where they were made. The most famous example of localized amyloidosis is Alzheimer’s disease, where amyloid plaques form in the brain.
It is not clear how amyloid actually causes organ damage and disease. Sheer bulk of deposited amyloid material can apparently cause problems, but even the heart is surprisingly tolerant of this. And the mass of amyloid in the brains of Alzheimer’s disease patients is quite low, although clearly brains are rather intolerant of damage. It seems that there’s something else going on. It’s possible that in some cases, the amyloid is a consequence of pathology, not its cause. Despite many years of research effort, scientists have not been able to explain how amyloid formation leads to Alzheimer’s disease, even though there is very strong evidence linking the two processes.
In systemic amyloid disease, though, treatments that stop amyloid deposition can alleviate disease. The success of precursor protein-directed therapies in transthyretin amyloidosis, for example, is very strong evidence for the involvement of amyloid in disease. A major challenge is diagnosing patients early enough to intervene, because these diseases are relentlessly progressive, but still quite rare. By the time a physician runs through the likely reasons for a patient’s symptoms and thinks to check for amyloid, the disease can be very advanced.
Research in amyloid disease focuses on a few broad areas. What are the fundamental chemical and physical processes that cause a few specific proteins to aggregate? What are the genetic factors that contribute to disease? How does protein misfolding and aggregation lead to cell death and organ failure? How can we intervene to prevent, or even reverse amyloid deposition?
We study a systemic amyloid disease called AL amyloidosis, where the precursor protein is an antibody light chain. This is one of the most common, and most-studied systemic amyloid diseases, but it’s also one of the most complex, because of each patient’s precursor protein is different, and each patient has their own unique constellation of symptoms.