Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Abstract

Abstract. Protein fibrillization is implicated in the pathogenesis of most, if not all, ageassociated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ' amyloid pore'. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

“…Our results demonstrated that TDP-43 oligomers are also heterogeneous. The dominant morphology resembles spherical oligomers found in Ab and a-synuclein oligomers 42 . The fact that they are also neurotoxic suggests full-length TDP-43 may possess a pathogenic mechanism similar to other amyloid pathologies.…”

“…2), indicating that the majority of the recombinant full-length TDP-43 proteins from two different sources readily formed large aggregates. As TDP proteinopathies are characterized by IB formation and high MW aggregates were found in the recombinant full-length TDP-43, we suspected that TDP-43 may form oligomers resembling the amyloid oligomers in amyloidosis 31 . Therefore, we employed the conformation-dependent antiamyloid oligomer-specific antibody, A11, generated against Ab oligomer mimics to examine the TDP-43 oligomers 13 .…”

“…The intermediate prefibrillar Ab oligomers have been found to correlate best with cognitive impairment and synaptic dysfunction 11 . Various assemblies and morphologies of Ab oligomer have been reported 40 in which pore-like oligomers have been suggested to form membrane permeable pores 31 and ion channels 41 . Our results demonstrated that TDP-43 oligomers are also heterogeneous.…”

Protein aggregation in bacteria: the thin boundary between functionality and toxicity

“…Protein aggregation in bacteria as Ab, a-synuclein, polyglutamine and IAPP, are able to form pores or single channels in membranes in vitro (Kagan et al, 2001;Quist et al, 2005;Lashuel & Lansbury, 2006). The small annular Ab and a-synuclein closely resemble the cytolytic b-barrel pore-forming bacterial toxins such as a-toxin, latrotoxin and aerolysin, suggesting a common mechanism of membrane interactions (Hotze et al, 2002).…”

Unraveling the mysteries of protein folding and misfolding

“…It is not clear how the species formed during amyloid fibril assembly cause cell death, and indeed whether the mechanism behind the toxicity is the same for all amyloid fibril-forming proteins. A number of hypotheses have been proposed, for example, that a soluble precursor forms a pore-like structure in cell membranes (the amyloid channel or amyloid pore) which culminates in neuronal death by unregulated membrane permeabilization (23,24). Others have suggested that the toxicity of pre-fibrillar amyloid species is due to the production of reactive oxygen species (e.g.…”