The term ‘amyloid’ was first used in 1854 by Rudolph Virchow to describe abnormal brain tissue that was stained by iodine, suggesting that it was starch-like. It was later discovered that the amyloid deposits, first named by Virchow, were in fact primarily proteinaceous. The definition of amyloid has since been expanded to include a large number of proteins that form a similar fibrillar ultrastructure. These protein fibrils share many structural characteristics despite having unrelated and dissimilar primary sequences. Amyloid fibrils are composed of proteins arranged in a cross β-sheet quaternary structure, where the β-strands are aligned perpendicular to the fibril axis. Amyloid typically has a straight, unbranched fiber morphology and is roughly 7.5-13 nm in diameter. When subjected to X-ray fiber diffraction, the fibrils exhibit reflections at 4.7 and 10 Å, the distances between β-strands and between β-sheets, respectively. Amyloid fibrils selectively bind the dyes thioflavin T (TfT) and Congo red, substantially enhancing the fluorescence quantum yield of TfT. Congo red bound to amyloid exhibits apple-green birefringence when viewed under polarized light.
The process of amyloid fibril formation is causatively linked to many diseases, including Alzheimer’s disease, Parkinson’s disease, Huntingon’s disease, and familial amyloidotic polyneuropathy and cardiomyopathy. Although the exact mechanism of toxicity and the identity of the toxic species remain unknown, there is strong genetic and pathologic evidence that the process of amyloidogenesis is closely linked to these maladies. The mechanisms by which proteins assemble into amyloid vary, as do the reasons why some people are more likely to develop amyloid diseases than others. Some of the proteins that form amyloid and putatively cause amyloid disease, such as Aβ, huntingtin, and α-synuclein, are thought to be intrinsically
disordered. These assemble into amyloid in a highly concentration dependent process to form a cross β-sheet amyloid aggregate. Other amyloidogenic proteins, such as transthyretin, β<sub>2</sub>-microglobulin, and the prion protein, exhibit well-defined native 3-dimensional structures and only form aggregates after partial unfolding or misfolding. Many amyloid diseases are familial, i.e. they are caused by mutations in genes encoding the protein that forms amyloid or a protein that is involved in the proteolytic processing of an amyloid precursor protein. For example, there are over one hundred point mutations in transthyretin that destabilize its native tetrameric fold, increasing the partially-folded monomer population and thus enhancing its amyloidogenicity, leading to familial amyloid polyneuropathy or cardiomyopathy. A point mutation at position 187 from an Asp to an Asn or Tyr in the protein gelsolin eliminates a Ca<sup>2+</sup> binding site, destabilizing that protein domain and making it susceptible to aberrant cleavage first by furin in the Golgi compartment and then by a membraneassociated type I matrix metalloprotease outside the cell, yielding 8 and 5 kDa fragments. These peptide fragments then aggregate into amyloid, enabled by glycosaminoglycans, resulting in familial amyloidosis of the Finnish type or gelsolin amyloid disease. Although specific mutations in some proteins can lead to earlyonset amyloidoses, e.g. the L55P mutation in transthyretin leads to familial amyloid polyneuropathy in the second decade, much more frequently wild-type proteins will aggregate and cause sporadic disease in the aged. It remains unclear why amyloid diseases tend to affect the elderly, although it is becoming more clear that signaling pathways that maintain the proteome and strongly influence aging either share common components or in some cases are one in the same. For example, the proteostasis network capacity, which is strongly influenced by the unfolded protein response and the heat shock response, strongly influences the etiology of these diseases. Additionally, how the formation of amyloid leads to the apparently unique phenotype of each disease is still not well understood; whether deposited amyloid fibrils or intermediates leading to that deposition cause disease and how those species exhibit toxicity to cells are current topics of investigation. Understanding what triggers the onset of sporadic amyloid diseases not associated with any known mutation and the factors that hasten disease progression is of great interest. Learning more about these factors should lead to knew treatment strategies for these diseases.
Reference:
Siegel, S. J. (2008). Structure and energetics of amyloid. The Scripps Research Institute.