Amyloid
Amyloid describes various types of protein aggregations that share specific traits when examined microscopically. The name amyloid comes from the early mistaken identification of the substance as starch based on crude staining techniques (amylum in Latin).Because amyloid plaques are generally the product of downhill or nucleation-dependent polymerizations, the phenotypes of genetically transmitted amyloid diseases are often inherited in an autosomal dominant fashion (Huntington's disease is in fact in most genetics texts the canonical autosomal dominant disease). The difference between aggressive amyloid diseases (which are usually the product of genetic mutation) and the senescent amyloid diseases (which sometimes occur for "wild-type" protein) can be attributed to the fact that these often result from "misfolded" conformations of the protein which aggregate. Naturally, evolution has selected the wild-type protein to avoid the misfolded conformation, often through tertiary or quaternary structure stabilization; mutations often lead to higher in vivo concentrations of aggregation precursor, through loss of stabilization effect or even (in the case of tertiary stabilization) cleavage from stabilizing domains.
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2 Non-disease amyloids 3 Histological staining for amyloid 4 Amyloid Biophysics 5 External links |
Diseases that feature amyloid deposition
It should be noted that 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 if they are instead a symptom downstream of a different ideopathic agent.Non-disease amyloids
Histological staining for amyloid
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 staning histology stains such as haematoxylin and eosin 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 was selected against.
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 arcoss more than one molecule. While the evolution and identification of amyloid is usually carried out by using fluorescent dyes, 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 each, corresponding to the interstrand distances in the beta sheet structure.
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, all humans have produce an amyloidogenic peptide associated with diabetes, but in rodentia, a proline is substituted in a critical location and amyloidogenesis does not occur. Cross-polymerization is a known phenomenon, and this is the putative cause between a link between diabetes and alzheimer's disease.
External links