Protein Aggregation Diseases: Toxicity of Soluble Prefibrillar Aggregates and Their Clinical Significance - Protein Misfolding and Cellular Stress in Disease and Aging - page 24

reported (reviewed in ( 3 )). The best known amyloid diseases
affect the brain and the central nervous system (e.g., Alzheimer's,
Parkinson's, Huntington, Creutzfeldt-Jakob diseases, and other
neurodegenerative conditions such as several ataxias) or periph-
eral tissues and organs (type-2 diabetes mellitus, several systemic
amyloidoses, dialysis-related amyloidosis). In the latter, the depos-
its are predominantly extracellular, whereas in most neurodegen-
erative diseases protein fibrillar polymers are found inside the
cells, either in the cytoplasm or in the nucleus ( 4 ).
The presence in tissue of fibrillar proteinaceous deposits of a
specific protein/peptide is a recognized hallmark of any peculiar
amyloid condition leading to suggest that a causative link must
exist between aggregate deposition and clinical symptoms (the
amyloid hypothesis). The latter is presently supported by many
biochemical and genetic studies ( 5-7 ) although the structural
features of the pathogenic aggregated species (mature fibrils, their
oligomeric precursors, or both) and the molecular basis of their
cytotoxicity are still under intense investigation ( 8-12 ). The poly-
peptides found aggregated in the differing amyloid diseases can
display either wild type sequences, as in the sporadic diseases, or
be variants resulting from genetic mutations associated with early-
onset, familial forms. The existence of the latter has provided sig-
nificant clues as to the origins of these pathologies indicating the
existence of a link between aggregation propensity of the mutant
protein and the time of appearance and severity of the clinical
signs of a specific disease ( 13, 14 ).
In the past, the idea was generally accepted that protein
aggregation into amyloid assemblies resulted from unusual con-
formational changes inherently related to some specific structural
features of the peptides and proteins associated with amyloid dis-
eases. This view was challenged in 1998, when it was first reported
that, under mild denaturing conditions, two different proteins
unrelated to any amyloid disease were able to aggregate in vitro
into ordered polymers comparable to the amyloid fibrils grown
from disease-associated peptides and proteins ( 15, 16 ). Soon after
that, a similar behaviour was described for other proteins ( 17 )
and subsequently confirmed for an increasing number of natural
proteins and peptides as well as for amino acid homopolymers
and very short synthetic peptides (( 18 ) and references therein,
( 19 )). These data led some authors to propose that amyloid
aggregation is associated with physicochemical properties inher-
ent to the shared covalent peptide backbone of any protein/
peptide, at variance with the sequences of their side-chains, whose
interactions primarily dictate a protein's specific fold ( 20 ).
Nevertheless, the properties of the side-chains affect profoundly
the propensities of proteins and peptides to generate amyloid
assemblies under given conditions and influence the structural
details of the latter.