(557a) Amyloid Assembly: Unveiling Complexity and Tapping Engineering Opportunities

Aggregation of an amyloidogenic protein, b-amyloid (Ab), into oligomeric and fibrillar aggregates is implicated in Alzheimer’s disease (AD). Similarly, formation of amyloid aggregates by a protein, a-synuclein (aS), is a causative factor for pathology of Parkinson’s disease (PD). Among different aggregate species, oligomeric forms of Ab and aS are most toxic, causing oxidative stress, inflammation and membrane permeabilization, as well as other detrimental effects. Despite recent progress in AD and PD pathology related to aggregation of Ab and aS, respectively, our understanding of molecular basis of these diseases is still incomplete. One important, yet mostly overlooked, factor is the occurrence of Ab-aS interaction, and consequent effects on aggregation as well as cellular manifestations. In the first half of this talk, I will share our recent findings on complexity associated with Ab-aS interactions and discuss implications of these molecular interactions.

An amyloid protein belongs to a group of intrinsically disordered proteins (IDPs). Due to high structural flexibility, occasionally coupled with functional roles, Nature often uses IDPs as structure-switching biosensors for rapid and specific signaling processes. Thus, IDPs may serve as a new source of proteins that can readily be engineered into molecular sensors with unique sensing behaviors. In the second half of my talk, I will describe our recent engineering effort to create a structurally flexible αS variant, PG65-MIMO (a PG65 variant with Multiple-Inputs and Multiple-Outputs), that rapidly generates distinct fluorescence responses to the three major αS conformers (monomers, oligomers, and fibrils).

Overall, my talk will illustrate important challenges to address to better understand complexity of amyloid diseases and present new engineering opportunities with IDPs.