The relationship between amyloid structure and cytotoxicity

Abstract

Self-assembly of proteins and peptides into amyloid structures has been the subject of intense and focused research due to their association with neurodegenerative, age-related human diseases and transmissible prion diseases in humans and mammals. Of the disease associated amyloid assemblies, a diverse array of species, ranging from small oligomeric assembly intermediates to fibrillar structures, have been shown to have toxic potential. Equally, a range of species formed by the same disease associated amyloid sequences have been found to be relatively benign under comparable monomer equivalent concentrations and conditions. In recent years, an increasing number of functional amyloid systems have also been found. These developments show that not all amyloid structures are generically toxic to cells. Given these observations, it is important to understand why amyloid structures may encode such varied toxic potential despite sharing a common core molecular architecture. Here, we discuss possible links between different aspects of amyloidogenic structures and assembly mechanisms with their varied functional effects. We propose testable hypotheses for the relationship between amyloid structure and its toxic potential in the context of recent reports on amyloid sequence, structure, and toxicity relationships.

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

“…27 C-terminal elongation of Ab40 to Ab42 and Ab43 has shown greater influence on the aggregation rates and toxicity. In Ab40 fibrils hydrophobic C-terminal face (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) of individual cross b-sheet units face towards each other to form dimer units which further interact to form higher order fibrils (striated-ribbon morphology in TEM). In this context, solid state nuclear magnetic resonance (ssNMR) has become one of the most effective and sought after method to study the structural aspects of Ab aggregates.…”

“…In this context, solid state nuclear magnetic resonance (ssNMR) has become one of the most effective and sought after method to study the structural aspects of Ab aggregates. 31 Riek et al presented a new structural model of Ab42 protofilaments where odd numbered amino acid residues of b1 (10-20) interact with even numbered residues of b2 (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) in the Ab42 unit. 28 Ab40 aggregates show U-shaped b-sheet confirmation where stretches of amino acid residues 12-24 and 30-40 are involved in intramolecular b-sheet formation.…”

De novo design of a biologically active amyloid

“…Still, only about 30 human proteins are known to be involved in amyloid-associated diseases (7,8). Moreover it is still not clear what determines amyloid toxicity in these diseases (8,9). Here we investigate whether an endogenously expressed protein that possesses amyloidogenic potential but aggregates neither under normal nor pathological conditions, can be induced to do so by seeding with a peptide consisting of an amyloidogenic fragment of its own sequence.…”

Proteotoxicity and Cardiac Dysfunction

“…134 The propensity of oligomers to be "sticky" and exhibit detergent-like qualities has been remarked upon by a number of groups and the oligomer's ability to interact with different membrane systems has been proposed to be intrinsic to their toxicity. 138,[142][143][144][145] In the heart, membrane integrity is obviously critical for the maintenance of cell viability. Disruption of either the plasma membrane or the other vital membrane-enclosed organelles such as mitochondria or T-tubules would clearly affect cardiomyocyte function.…”