Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates

Abstract

Diseases such as type 2 diabetes, Alzheimer’s and Parkinson’s share as common feature the accumulation of mis-folded disease-specific protein aggregates into fibrillar structures, or plaques. These fibrils may either be toxic by themselves, or act as reservoirs for smaller cytotoxic oligomers. This suggests to investigate molecules as potential therapeutics that either reduce fibril formation or increase fibril stability. One example is rat amylin, which can inhibit aggregation of human amylin, a hallmark of type 2 diabetes. In the present paper, we use molecular dynamics to compare the stability of various preformed aggregates, built out of either human amylin, rat amylin, or mixtures of both. We considered two types of fibril-like oligomers: a single-layer in-register conformation, and a double-layer conformation in which the first U-shaped layer consists of rat amylin and the second layer of human amylin. Our results explain the weak amyloid-inhibiting properties of rat amylin and suggest that membrane leakage due to pore formation is responsible for the toxicity of rat amylin observed in a recent experiment. Together, our results put in question the use of rat amylin or the similar FDA approved drug pramlintide as an inhibitor of human amylin aggregation. They also point to mixed human-rat amylin fibril-like oligomers as possible model-systems for studies of amyloid formation that involve cross-species transmission.

Stability of Amyloid Oligomers

“…The structural instability of rat amylin fibrils (due to proline residues in the C terminus) makes N-terminal head-to-head interface between the β-sheets of rat/human amylin mixed fibril more stable than fibrils that are organized through CC terminal interfaces. The simulation points to a possible mechanism for the weak inhibitor activity of rat amylin and for the formation of rat amylin amyloids when provided with human amylin fibrils as template (Berhanu & Hansmann, 2014) that is in agreement with experimental data (Middleton et al, 2012;Young, Cao, Raleigh, Ashcroft, & Radford, 2014).…”

“…In another project, we have used molecular dynamics simulations (Berhanu & Hansmann, 2014) to explain the weak inhibition of human amylin aggregation by rat amylin that was observed in experiments. For this purpose, we have compared the stability of fibril aggregates built from human amylin, rat amylin, and mixtures of both.…”

“…However, none of the experimental fibril structures of Aβ (PDB ID: 2M4J and 2LMN) and human amylin (Wiltzius et al, 2008) contain water. Water residing in the hydrophilic cavities of homo-oligomers and hetero-oligomers Berhanu & Hansmann, 2014). Snapshots for (A) wild-type Aβ ¼ brown (dark gray in the print version); (B) wild-type human amylin ¼ blue (black in the print version); (C) wild-type rat amylin ¼ magenta (dark gray in the print version); (D) wild-type Aβ-amylin aggregates complex; Aβ ¼ brown (dark gray in the print version) and amylin ¼ blue (gray in the print version); (E) wild-type human amylin in complex with rat amylin aggregates; human amylin ¼ blue (black in the print version) and rat amylin ¼ magenta (dark gray in the print version); (F) wild-type human amylin in complex with Y37L mutant; human amylin ¼ blue (light gray in the print version) and Y37L mutant ¼ brown (dark gray in the print version).…”

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

“…Visual inspection of the two-fold structures indicates that the larger steric zipper interface stabilizes such contacts much better than in the three-fold fibril models characterized by small steric zipper (with Ca-Ca at interface being 19.0 Å ) and less efficient packing between U-shaped units. 27,28 However, the Ca-Ca distance between H 13 and V 40 in the termini of the in vitro two-fold model is larger, indicating flexibility of residues at edge. Hence, our simulations imply that larger number of interface contacts in the twofold systems leads to their higher stability over the three-fold systems, with the in vivo three-fold being the least stable (Figs.…”

Polymorphic Associations and Structures of the Cross-Seeding of Aβ1–42 and hIAPP1–37 Polypeptides

“…Recently, more biologically importantly and interesting findings have reported that different amyloid peptides can interact with each other to form hybrid amyloids containing conformationally cross-β-sheet structures similar to homo-amyloids [17][18][19][20][21] . Typical examples of these hybrid amyloids were comprised of β-amyloid (Aβ)-islet amyloid peptides (IAPP), Aβ-tau, Aβ-prion, human IAPP-rat IAPP, and tau-synuclein amyloids [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] . These important findings imply a potential pathological link between different amyloid diseases 37 .…”