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Amyloidosis
 

Amyloids are various types of insoluble fibrous protein aggregations sharing specific traits when examined microscopically. The name amyloid comes from the early mistaken identification of the substance as starch (amylum in Latin), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.

Amyloid deposits are extracellular, thioflavin-positive, and exhibit apple-green birefringence when stained with congo red when seen under a polarizing microscope. Other indicators exist, such as serum amyloid P component binding. Since these are indirect indicators, biophysicists have redefined amyloid using a canonical set of biophysical characteristics (see below), and this seems to cause a low level of conflict between histologists and biophysicists.

The phenotypes of genetically transmitted amyloid diseases are often inherited in an autosomal dominant fashion. Sometimes, the difference between aggressive amyloid diseases and senescent amyloid diseases is due to a mutation that makes the protein more prone to aggregation. Most commonly seen are point mutations, which affect the cohesiveness of the protein and promote misfolding; other mutations cause aggregation-prone pieces of the protein to be cleaved off from the rest of the protein.

Amyloids are present in some neurodegenerative diseases but play a normal productive role in processes such as melanin formation.*

Diseases featuring amyloid

In almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or instead a symptom downstream of a common idiopathic agent. The associated proteins are indicated in parentheses. Note that amyloidosis by itself usually refers to AA amyloidosis, but any disease which presents amyloid deposition is technically an amyloidosis. CJD, Alzheimer's and diabetes are almost never referred to as amyloidoses.

Non-disease amyloids

  • Native amyloids in organisms
    • Curli E. coli Protein (curlin)
    • Yeast Prion * {Ref Nakayashiki, PNAS, 2005}
    • Malarial coat protein
    • Spider silk
    • Mammalian melanosomes (pMel)
    • Tissue plasminogen a (tPA), a hemodynamic factor
  • Proteins and peptides known to make amyloid without any known disease
    • Calcitonin
  • Proteins and peptides engineered to make amyloid

Amyloid biophysics

The amyloid fold is characterized by a cross-beta sheet quaternary structure; that is, a monomeric unit contributes a beta strand to a beta sheet, which spans across more than one molecule. While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the "gold-standard" test to see if a structure is amyloid is by placing a sample in an X-ray diffraction beam; there are two characteristic scattering bands produced at 4 and 10 angstroms (0.4 nm and 1.0 nm}, corresponding to the interstrand and stacking distances in beta sheets. It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands.

Amyloid polymerization is generally sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline. For example, humans produce an amyloidogenic peptide associated with type II diabetes, but, in rodentia, a proline is substituted in a critical location and amyloidogenesis does not occur.

There are two broad classes of amyloid-forming polypeptide sequences. Glutamine rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as Huntington's disease. Glutamines can aggregate peptides into a beta-sheet conformation, where the structure is braced by intrastrand hydrogen bonding between glutamine amide carbonyls and nitrogens. In general, for these diseases toxicity correlates with glutamine content. This has been observed in studies of onset age for Huntington's disease (the longer the polyglutamine sequence, the sooner the symptoms appear), and has been confirmed in a C. elegans model system with engineered polyglutamine peptides.

Other polypeptides and proteins such as amylin and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by hydrophobic association.

For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is a phenomenon observed in vitro. This phenomenon is important since it would explain interspecies prion propagation and differential rates of propagation, as well as a statistical link between Alzheimer's and diabetes. In general, cross-polymerization is more efficient the more similar the peptide sequence, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" which prevent polymerization. Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.

Beta-2 microglobulin is one of the proteins thought to form amyloid deposits.

Histological staining

Amyloid is typically identified by a change in the fluorescence intensity of planar aromatic dyes such as Thioflavin T or Congo Red. This is generally attributed to the environmental change, as these dyes intercolate between beta-strands. Congophillic amyloid plaques generally cause apple-green birefringence, when viewed through crossed polarimetric filters. To avoid nonspecific staining, histology stains, such as haematoxylin and eosin stain, are used to quench the dyes' activity in other places where the dye might bind, such as the nucleus. The dawn of antibody technology and immunohistochemistry has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the antibody recognizes.

External links

Amylose (maladie) | Amyloidoza | Amyloid

Anatomical pathology | Structural proteins

 

This article is licensed under the GNU Free Documentation License. It uses material from the "Amyloid".

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