ConspectusThe aberrant misfolding and aggregation of peptides
and proteins
into amyloid aggregates occurs in over 50 largely incurable protein
misfolding diseases. These pathologies include Alzheimer’s
and Parkinson’s diseases, which are global medical emergencies
owing to their prevalence in increasingly aging populations worldwide.
Although the presence of mature amyloid aggregates is a hallmark of
such neurodegenerative diseases, misfolded protein oligomers
are increasingly recognized as of central importance in the pathogenesis
of many of these maladies. These oligomers are small, diffusible species
that can form as intermediates in the amyloid fibril formation process
or be released by mature fibrils after they are formed. They have
been closely associated with the induction of neuronal dysfunction
and cell death. It has proven rather challenging to study these oligomeric
species because of their short lifetimes, low concentrations, extensive
structural heterogeneity, and challenges associated with producing
stable, homogeneous, and reproducible populations. Despite these difficulties,
investigators have developed protocols to produce kinetically, chemically,
or structurally stabilized homogeneous populations of protein misfolded
oligomers from several amyloidogenic peptides and proteins at experimentally
ameneable concentrations. Furthermore, procedures have been established
to produce morphologically similar but structurally distinct oligomers
from the same protein sequence that are either toxic or nontoxic to
cells. These tools offer unique opportunities to identify and investigate
the structural determinants of oligomer toxicity by a close comparative
inspection of their structures and the mechanisms of action through
which they cause cell dysfunction.This Account reviews multidisciplinary
results, including from
our own groups, obtained by combining chemistry, physics, biochemistry,
cell biology, and animal models for pairs of toxic and nontoxic oligomers.
We describe oligomers comprised of the amyloid-β peptide, which
underlie Alzheimer’s disease, and α-synuclein, which
are associated with Parkinson’s disease and other related neurodegenerative
pathologies, collectively known as synucleinopathies. Furthermore,
we also discuss oligomers formed by the 91-residue N-terminal domain
of [NiFe]-hydrogenase maturation factor fromE. coli, which we use as a model non-disease-related protein, and by an
amyloid stretch of Sup35 prion protein from yeast. These oligomeric
pairs have become highly useful experimental tools for studying the
molecular determinants of toxicity characteristic of protein misfolding
diseases. Key properties have been identified that differentiate toxic
from nontoxic oligomers in their ability to induce cellular dysfunction.
These characteristics include solvent-exposed hydrophobic regions,
interactions with membranes, insertion into lipid bilayers, and disruption
of plasma membrane integrity. By using these properties, it has been
possible to rationalize in model systems the responses to pairs of
toxic and nontoxic oligomers. Collectively, these studies provide
guidance for the development of efficacious therapeutic strategies
to target rationally the cytotoxicity of misfolded protein oligomers
in neurodegenerative conditions.