Studies on amyloid aggregation and cross-species prion transmission

Protein aggregation;Amyloid;Prion;Hofmeister;Species barrier

Sharma, Aditi ; Bommarius, Andreas S. Chemical and Biomolecular Engineering Chernoff, Yury O. Behrens, Sven H. Champion, Julie A. Finn, M. G. ; Bommarius, Andreas S.

University:Georgia Institute of Technology

Department:Chemical and Biomolecular Engineering

关键词: Protein aggregation;    Amyloid;    Prion;    Hofmeister;    Species barrier;   

Others  :  https://smartech.gatech.edu/bitstream/1853/61123/1/SHARMA-DISSERTATION-2018.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

Ordered aggregation of proteins into amyloids (and their transmissible versions, prions) has been shown to result in several neurodegenerative diseases in humans and other mammals. While the effect of ions has been extensively studied in the context of measuring the stability of protein formulations and formation of disordered aggregates, there is limited information available on the effect of ions on the formation of ordered amyloid aggregates. In this thesis, we have investigated in detail the effect of presence of ionic co-solutes on the aggregation of amyloids. Here, we have studied the efficiency of cross-transmission of the NM fragment of Sup35 prion protein, between three closely related species of the Saccharomyces sensu stricto group. Using anions of the Hofmeister series, we discerned the relative effects of protein sequence, seed conformation, and environment on the cross-species transmission of this protein. Further, through investigation of the aggregation of Amyloid beta-42 (Aβ42) and Sup35NM in the presence of anions we have uncovered interesting differences in their aggregation behavior suggesting key differences in the aggregation mechanism of these proteins. Lastly, we developed a computational model for amyloid aggregation kinetics and used it for global fitting of Sup35NM amyloid aggregation data. In all, this thesis expands the current knowledge of ion-specific effects on aggregation of amyloid proteins as well as of the mechanisms of amyloid aggregation.