Protein Aggregation Diseases: Toxicity of Soluble Prefibrillar Aggregates and Their Clinical Significance - Protein Misfolding and Cellular Stress in Disease and Aging - page 25

In spite of the inherent propensity to aggregate of any
polypeptide chain, only a very limited number of proteins and
peptides are found aggregated in specific diseases under normal
conditions. Such an apparent paradox can be explained consid-
ering the highly cooperative nature of the process by which a
protein gains its native structure, and the structural evolutive
adaptations aimed at increasing the resistance of natural proteins
against aggregation ( 21 ). The evolution of the complex mecha-
nisms and quality control of folding also allows natural proteins
to escape the tendency to aggregate for significant lengths of time
( 22 ). However, the build-up of the precursor, aggregation-prone,
species that nucleate rapid aggregate growth, can be triggered by
any alteration of a protein's levels or structure (increased synthe-
sis or reduced degradation, presence of specific mutations) or by
minor, even subtle, changes in the environmental conditions. The
latter can include heat shock, oxidative stress or chemical modifi-
cations, alterations of the intracellular macromolecular crowding,
presence of suitable surfaces, absence of stabilizing ligands, any
impairment of the quality control of protein folding in the cell,
and others ( 23 ).
Finally, increasing efforts are presently dedicated at investi-
gating the structural features and the structure-toxicity relation of
the soluble oligomeric precursors arising in the path of fibril for-
mation. In fact, it is increasingly recognised that these unstable,
dynamic assemblies are endowed with the highest toxicity to cells
thus featuring these as the main factor responsible for cell impair-
ment in amyloid diseases. This chapter will focus on the structural
and biochemical features, as well as the biological and clinical sig-
nificance, of these assemblies.

2. Soluble
Pre-fibrillar
Aggregates
Are Generated in
the Path of Protein
Fibrillization
In Vitro and In Vivo

Amyloid assemblies are presently considered the main culprits of
cell impairment in affected tissues in a number of degenerative
diseases including several systemic amyloidoses, type II diabetes
mellitus, Alzheimer's, Parkinson's and prion diseases ( 1-4 ). The
study of the amyloid structure has therefore been a main focus in
the investigation of the molecular basis of amyloid diseases.
However, although considerable information has recently been
gained on the structural features of the ordered b-sheet-rich core
of amyloid fibrils and their supramolecular organization ( 24-26 )
there is still a severe lack of knowledge on the structural features
of fibril precursors. Therefore, a key issue in the investigation of
the amyloid structures is the description of either the growth
mechanism from their monomeric precursors and the structural
features of their intermediates.