Fundamentals of cross-seeding of amyloid proteins: an introduction

Abstract

Misfolded protein aggregates formed by the same (homologous) or different (heterologous/cross) sequences are the pathological hallmarks of many protein misfolding diseases (PMDs) including Alzheimer's disease (AD) and type 2 diabetes (T2D).

Structural and molecular basis of cross-seeding barriers in amyloids

“…have a prion-like behaviour (4,5) and can propagate under different structural conformations also known as prion 'strains', which may be associated with distinct phenotypes of the pathology (6)(7)(8)(9). The cross-talk between an infectious amyloid conformation (prion strain) and a naive homologous or heterologous amyloidogenic sequence, referred to as 'cross-seeding' (10,11), is a critical event in prion biology, representing the key aspect of infectivity. Amyloid cross-seeding could play a role in the aetiology (12) and pathogenesis of various proteinopathies (13,14).…”

Aromadendrin: a dual amyloid promoter to accelerate fibrillization and reduce cytotoxicity of both amyloid-β and hIAPP

“…More importantly, the sequence-independent promotion effect of aromadendrin on Ab and hIAPP could also be extended to other amyloid peptides for fighting against different amyloid diseases. Given that (i) this work has demonstrated the promotion effect of aromadendrin on both Ab and hIAPP aggregation and (ii) our and other previous works have demonstrated the cross-seeding between Ab and hIAPP, 37,[52][53][54] it is of great interest to study the effect of aromadendrin or other dual inhibitors/promoters on the cross-seeding of Ab and hIAPP in the future, which may provide alternative pharmaceutical strategies to block the cross-seeding between different amyloid peptides so as to prevent their pathological transmission between cells and tissues. In addition, given the limited progress on developing amyloid promoters, it is still challenging to discover therapeutic promoters capable of (i) strong specific binding affinity towards monomeric or oligomeric amyloids, (ii) rapid structural conversion into b-sheet-rich structures, or (iii) producing off-pathway promoter-amyloid aggregates for minimal cytotoxicity.…”

“…Among different PMDs, AD and T2D are connected by some common molecular denominators, including inflammation, defective insulin signaling, and mitochondrial dysfunction. 37 A number of molecular dynamics (MD) simulations discovered that the binding of insulin with Ab and hIAPP aggregates affected the pathological aggregation of Ab and hIAPP. 38,39 MD simulations also revealed that Ab and hIAPP can cross-seed each other to form enlongated fibrils and laterally associated fibrils, which in turn exacerbate the neurodegenerative process.…”

“…Time-dependent far-UV CD spectra for (a1) Ab 42(25 mM) and (b1) hIAPP37 (25 mM) in the absence and presence of aromadendrin at different amyloid : aromadendrin molar ratios of 1 : 1, 1 : 2, and 1 : 5, with quantitative analysis of the secondary structure contents of the (a2) Ab 42 and (b2) hIAPP 37 systems.Paper Materials Advances Open Access Article. Published on 30 June 2020.…”

Crosstalk Between Alpha-Synuclein and Other Human and Non-Human Amyloidogenic Proteins: Consequences for Amyloid Formation in Parkinson’s Disease

“…In similarity, for pre-formed amyloid fibers of other amyloidogenic proteins, they may either seed aS monomers to aggregate faster (heterologous seeding) or they may inhibit aS monomers to form amyloids. In all the cases, this requires interactions between different amyloidogenic proteins and such are proposed to be governed by 'conformational selection and population shift', meaning that one or both proteins need to be flexible and able to adjust their conformations to compatible binding states [57]. Using high-resolution methods (solid-state NMR and cryo-EM), aS amyloid fibers have been found to adopt different morpholo- gies (sometimes called strains) depending on the aggregation conditions.…”