A new genetic approach for studying prions and other pathogenic protein aggregate

Harvard Medical School, Boston MA

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Linked publications & trials

Abstract

Abstract[unreadable] Prions are infectious, self-propagating protein aggregates that have been implicated in a number of[unreadable] devastating neurodegenerative diseases known as transmissible spongiform encephalopathies. In humans, the[unreadable] most common TSE, Creutzfeldt-Jakob disease, typically strikes without warning, leading to death within 1 year[unreadable] of diagnosis for 90% of patients. The TSEs have been attributed to a specific cellular protein (PrP) that has the[unreadable] potential to convert to a highly structured, ? sheet-rich aggregated form (referred to as amyloid) that is thought[unreadable] to be the infectious agent. With no therapies that can affect either the outcome or progress of the disease, new[unreadable] experimental avenues are crucial.[unreadable] The objective of the proposed research is to mobilize bacterial genetics as a new experimental system for[unreadable] studying prion behavior. Having shown that the E. coli cytoplasm can support the formation of prion-like[unreadable] aggregates, we propose to develop a set of transcription-based genetic assays that can detect conversion of[unreadable] protein domains to the prion state. Using these assays, we will conduct mutant screens to identify cellular[unreadable] chaperones and other factors that can affect the prion process. Because of the evolutionary conservation of[unreadable] chaperone proteins, such screens may uncover potential new drug targets relevant to mammalian disease.[unreadable] We will also use bacteria-based genetic assays to screen bacterial genomes as well as the genomes of higher[unreadable] organisms (including mammals) for novel prion proteins. The discovery of bacterial prions could have[unreadable] profound implications for human health, particularly in the context of host-pathogen interactions. Finally, we[unreadable] envision using bacteria-based genetic assays to screen for small molecules that can hinder conversion to[unreadable] and/or propagation of the prion state. While our primary focus is prion disease, the tools we aim to develop[unreadable] should also be applicable to the large number of non-infectious neurodegenerative diseases that are[unreadable] associated with the formation of amyloid aggregates.