261213 Modulation of Amyloid Aggregation by Engineering the Sequence Connecting Beta-Strand Forming Domains

Tuesday, October 30, 2012: 10:18 AM
Westmoreland West (Westin )
Yang Hu1, Michael Hernandez1, Ahra Ko2 and Jin Ryoun Kim1, (1)Chemical and Biomolecular Engineering, Polytechnic Institute of New York University, Brooklyn, NY, (2)Chemical and Biological Engineering, Polytechnic Institute of New York University, Brooklyn, NY

Aggregation of amyloidogenic proteins, implicated in the pathology of various neurodegenerative diseases, such Alzheimer’s disease and Parkinson’s disease, produces fibrils where layers of parallel, in-register beta sheet-loop-beta sheets are formed. The effects of sequence variation in the loop forming region (referred to as the linker region) on amyloid aggregation have yet to be systematically studied. In the study presented here, we created and characterized variants of alpha synuclein (alphaS) and beta amyloid (Abeta) containing mutations in linker regions.

Our results with alphaS variants indicate that while physicochemical properties of the linker region evaluated based on an intrinsic property of a single amino acid still play a significant role in aggregation, additional factors may also determine aggregation of alphaS linker mutants. Our analyses suggest that these factors may include a pairwise potential for parallel in-register beta sheet formation. A linker variant displaying significantly reduced self-aggregation interfered with alphaS aggregation by inhibiting conversion of alphaS soluble species to alphaS insoluble fibrils.

Our results with Abeta variants indicate that a propensity to form oligomers may be changed by local sequence variation in the Abeta linker region without mutating the charged residues. Strikingly, one Abeta linker variant rapidly formed protofibrillar oligomers, which did not convert to fibrillar aggregates in contrast to Abeta aggregating to fibrils under similar incubation conditions. Moreover, our results suggest that molecular forces critical in oligomerization and fibrillization may differ at least for those involved in the linker region. When co-incubated with Abeta, some Abeta linker variants were found to induce accumulation of Abeta oligomers.

Taken together, our results suggest that engineering of the linker region may represent a novel approach to control amyloid aggregation and create amyloid aggregation modulators.

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