Final Activity Report Summary - AMYLOID FIBRIL (Hydrogen deuterium exchange and amyloid fibril formation)
A range of human degenerative conditions, including Alzheimer's disease and type II diabetes, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils. Amyloid fibril formation requires often the population of at least partially unfolded states, these then go on to form aggregates that evolve into protofilaments which eventually give rise to mature amyloid fibrils.
At the time of starting the grant, we were working on a H/D exchange protocol that had been developed to identify the structured core of the amyloid fibrils and extending it to learn about the dynamic nature of amyloid fibrils. The results have revealed that, exchange is dominated not by solvent accessibility but by a mechanism of dissociation and re-association that results in the recycling of molecules within the fibril population. The dynamic nature of the fibrils, and the ability to determine the parameters that define this behaviour, provide new insights into the properties of amyloid fibrils and have profound implications for the design of therapeutic strategies directed against amyloid disease.
Evidence from several groups suggests that the early formed aggregates, rather than the mature amyloid fibrils, are responsible for the onset of the disease. One of the objectives of this proposal was to extend the applications of this H/D exchange study to characterize the structure and dynamics of the various aggregated states and protofilaments. After this grant, preliminary results are revealing that indeed the structure of the different species present during the process of aggregation can be studied using a modified H/D exchange protocol in which the structural information on the aggregates and protofilaments is obtained indirectly from the analysis of the amyloid fibrils. Knowledge of the structural properties of each of the states accessible along fibril formation is essential to understand the mechanism of amyloid fibril formation and to guide on-going drug discovery efforts.
At the time of starting the grant, we were working on a H/D exchange protocol that had been developed to identify the structured core of the amyloid fibrils and extending it to learn about the dynamic nature of amyloid fibrils. The results have revealed that, exchange is dominated not by solvent accessibility but by a mechanism of dissociation and re-association that results in the recycling of molecules within the fibril population. The dynamic nature of the fibrils, and the ability to determine the parameters that define this behaviour, provide new insights into the properties of amyloid fibrils and have profound implications for the design of therapeutic strategies directed against amyloid disease.
Evidence from several groups suggests that the early formed aggregates, rather than the mature amyloid fibrils, are responsible for the onset of the disease. One of the objectives of this proposal was to extend the applications of this H/D exchange study to characterize the structure and dynamics of the various aggregated states and protofilaments. After this grant, preliminary results are revealing that indeed the structure of the different species present during the process of aggregation can be studied using a modified H/D exchange protocol in which the structural information on the aggregates and protofilaments is obtained indirectly from the analysis of the amyloid fibrils. Knowledge of the structural properties of each of the states accessible along fibril formation is essential to understand the mechanism of amyloid fibril formation and to guide on-going drug discovery efforts.