Molecular mechanisms of amyloid disaggregation

Abstract

Introduction: Protein aggregation and deposition of uniformly arranged amyloid fibrils in the form of plaques or amorphous aggregates is characteristic of amyloid diseases. The accumulation and deposition of proteins result in toxicity and cause deleterious effects on affected individuals known as amyloidosis. There are about fifty different proteins and peptides involved in amyloidosis including neurodegenerative diseases and diseases affecting vital organs. Despite the strenuous effort to find a suitable treatment option for these amyloid disorders, very few compounds had made it to unsuccessful clinical trials. It has become a compelling challenge to understand and manage amyloidosis with the increased life expectancy and ageing population.

Objective: While most of the currently available literature and knowledge base focus on the amyloid inhibitory mechanism as a treatment option, it is equally important to organize and understand amyloid disaggregation strategies. Disaggregation strategies are important and crucial as they are present innately functional in many living systems and dissolution of preformed amyloids may provide a direct benefit in many pathological conditions. In this review, we have compiled the known amyloid disaggregation mechanism, interactions, and possibilities of using disaggregases as a treatment option for amyloidosis.

Methods: We have provided the structural details using protein-ligand docking models to visualize the interaction between these disaggregases with amyloid fibrils and their respective proposed amyloid disaggregation mechanisms.

Results: After reviewing and comparing the different amyloid disaggregase systems and their proposed mechanisms, we presented two different hypotheses for ATP independent disaggregases using L-PGDS as a model.

Conclusion: Finally, we have highlighted the importance of understanding the underlying disaggregation mechanisms used by these chaperones and organic compounds before the implementation of these disaggregases as a potential treatment option for amyloidosis.

Keywords: Amyloids; Chaperones; Disaggregation; Protein aggregation; Protein folding and misfolding.