Effect of trehalose on different stages of protein aggregation: in search of its therapeutic potential against neurodegenerative diseases

 

Nidhi Katyal, Shashank Deep

Department of Chemistry, Indian Institute of Technology, Delhi, New Delhi 110016, India

 

Abstract

Every protein under suitable conditions have intrinsic tendency to aggregate. The ramification of this assimilation process in human body is the emergence of neurodegenerative diseases. α-synuclein is one such intrinsically disordered protein which is involved in the pathogenesis of Parkinsons disease. Various additives are known to subvert this phenomenon and can be useful in the design of therapeutics. The diversity and complexity in the pathway chosen by different proteins to aggregate poses constraints in gaining a consensus view about effect of an additive. In this perspective, we have described how the complex aggregation pathway can be simplified broadly into three prominent steps common to all proteins. Using both experimental and computational tools we have tested the effect of Trehalose (an osmolyte and a widely accepted protein stabilizer) on the cascade of events leading to fibrillation process of α-synuclein. Our data suggests that trehalose triggers the onset of aggregation process of α-synuclein by influencing the conformational dynamics of the monomeric protein. It binds to the sidechain of the acidic C-terminal of the protein and stabilizes its aggregation prone extended conformer with fewer long range intra-chain interactions. It however, marginally decelerates the rate of encounter of these monomers. Subsequent β-sheet containing oligomers susceptible to form fibrils, are also favoured under trehalose regime. Paradoxically, the total fibrillar load was still promisingly less, since it accelerates the competing pathway towards formation of amorphous aggregates. We have finally proposed a model describing the events involved in α-synucleins aggregation pathway and their perturbation by trehalose. Rate constants of the formation of various species are compared under both the conditions. The findings could be correlated to few physical properties of trehalose, which were further examined on other protein systems. The most intriguing observation that is contemplated from all these studies was that some of the speculations seem to be ubiquitous to all the proteins/peptides. An extensive testing of different drug-protein interactions on these lines is thus required in future to acquire a consolidated view about therapeutic potential of any drug. 

 

References

 

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