Protein Aggregation Diseases: Toxicity of Soluble Prefibrillar Aggregates and Their Clinical Significance - Protein Misfolding and Cellular Stress in Disease and Aging - page 34

displaying different conformations ( 40, 41, 44, 104, 105 ) possibly
as a consequence of their growth under slightly different cell/
tissue conditions.
6. Conclusions
Significant information has been reported in recent years on
the biophysical and molecular determinants of protein folding,
misfolding, and aggregation, the structural features of amyloid
aggregates and the biochemical and physiologic effects they pro-
duce into exposed cells. In particular, the molecular basis of the
toxicity of small aggregates appearing during the early stages of
protein/peptide fibrillization appears to display shared charac-
teristics in the different systems that have been studied so far,
including aggregates grown from disease-associated and disease-
unrelated proteins and peptides. Present knowledge depicts a
scenario whereby, in most cases, the misfolded monomers or their
pre-fibrillar oligomers appear to be the main factor responsible
for amyloid cytotoxicity that often can be traced back to a few
shared, early biochemical modifications. Presently, amyloid cyto-
toxicity appears, at least in most cases, to require the interaction
of misfolded proteins and their early aggregates with the cell mem-
branes, with alterations of physical, chemical, and biochemical
features of the latter. Such interaction triggers complex cascades of
biochemical modifications starting with the alteration of the intra-
cellular ion content, redox state and energy load eventually culmi-
nating with cell death.
Much must still be learnt about these key points. For exam-
ple, increased information on the site(s) of a cell where those
interactions occur as well as on the existence of amyloid receptors
or preferential interaction sites is needed. Nonetheless, the idea is
steadily gaining support that the most toxic species are the oli-
gomers arising in the initial steps of protein aggregation. The key
role played in most cases by biological surfaces, particularly mem-
branes, in the onset of the chain of events starting with protein
misfolding and aggregation and culminating with cell death is
also emerging.
Acknowledgements
The author gratefully acknowledges financial support from the
Ente Cassa di Risparmio di Firenze and Italian MURST (PRIN
Project 2007XY59ZJ_001).