Abstract
Most neurodegenerative diseases such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, etc. are caused by inclusions and plaques containing misfolded protein aggregates. These protein aggregates are essentially formed by the interactions of either the same (homologous) or different (heterologous) sequences. Several experimental pieces of evidence have revealed the presence of cross-seeding in amyloid proteins, which results in a multicomponent assembly; however, the molecular and structural details remain less explored. Here, we discuss the amyloid proteins and the cross-seeding phenomena in detail. Data suggest that targeting the common epitope of the interacting amyloid proteins may be a better therapeutic option than targeting only one species. We also examine the dual inhibitors that target the amyloid proteins participating in the cross-seeding events. The future scopes and major challenges in understanding the mechanism and developing therapeutics are also considered. Detailed knowledge of the amyloid cross-seeding will stimulate further research in the practical aspects and better designing anti-amyloid therapeutics.
Highlights
Amyloids are the aggregates of proteins that are insoluble and resistant to degradation.The formation of amyloids is generally associated with diseases collectively known as amyloidosis, though some amyloids do have functional roles Castellano and Shorter [1–3].Several protein misfolding diseases (PMDs) are associated with the presence of amyloids, which are considered to be the hallmark of these diseases
Solid-state nuclear magnetic resonance, a technique widely used for studying the structure of amyloids, was performed on amyloid fibrils of Aβ to show that β-sheets within the protofilaments can be arranged in parallel or antiparallel orientations [4]
A large number of studies suggest that the oligomeric intermediates that are formed during the aggregation process are toxic, and their interactions with cell membranes lead to cellular damages and cell death
Summary
Amyloids are the aggregates of proteins that are insoluble and resistant to degradation. Several protein misfolding diseases (PMDs) are associated with the presence of amyloids, which are considered to be the hallmark of these diseases. The process of cross-seeding can either be homologous, i.e., seeds of the same protein, or they can be heterologous, i.e., seeds of one protein catalyzing the fibrillation of a different protein [12]. Cross-seeding aggregation between different amyloid proteins has been proposed to explain the presence of more than one misfolded protein in one disease and the coexistence of more than one PMD in the same individual [13,14]. In the case of coaggregation, two proteins can polymerize together to form a mixed aggregate or fibrils or polymerize separately into distinct aggregates or fibrils
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