The World of Functional Amyloid - The Functional Fold: Amyloid Structures in Nature - page 7

causes amyloid diseases, although this so-called amyloid hypothesis
remains unproven. Amyloid diseases affect a diverse array of organs
and tissues because the location and extent of amyloid formation are
defined by the unique physiological and biophysical parameters of
the amyloidogenic protein involved.

14

Interestingly, amyloid diseases can either arise spontaneously or
be the result of mutation. In cases such as transthyretin amyloidosis,
deposition of the wild-type protein can cause disease in an idiopathic
fashion, especially in old age, while specific mutations lead to early-
onset forms of the disease.

15

In cases such as gelsolin amyloidosis,
disease appears to arise only from the presence of mutations in the
gelsolin protein.

16
A significant challenge for the amyloid field has been in the
understanding of how the process of amyloidogenesis causes
tissue damage. Amyloid, especially oligomeric amyloidogenic inter-
mediates, have been shown to be toxic to cells in culture,

17,18

but
the mechanism of this acute toxicity and its relevance to the slow,
progressive tissue damage observed in amyloid disease remains
elusive. A significant hindrance is the fact that amyloid encompasses
a continuum of structures from small oligomers to fully formed fibres
that are in equilibrium and therefore difficult to isolate and study
independently. This has confounded efforts to positively identify a
particular toxic amyloid structure and its mode of action. One theory
suggests that pore-like amyloid oligomers capable of compromising
membrane integrity might be responsible for the tissue damage
observed in amyloid diseases.

19-21

β

oligomers
appear to disrupt synaptic plasticity and have been proposed as an
important causal factor of Alzheimer's disease pathology.

Alternatively, A

22

1. Amyloid Is a Functional Protein

Quaternary Structure

Given the toxicity of amyloid precursors and their apparent role in
disease, as well as the ability of fibres to mechanically compromise
organ function, the first reports of functional amyloid were quite
surprising. Functional amyloid was identified initially in a number
of lower organisms including bacteria,

1,23 24-28 29-30

fungi, and insects

and more recently in algae (Table 1.2). Additionally,

several functional amyloid candidates have been reported,

31

and humans

32

33-35