Investigating the Effect of Insulin on the Non-Amyloid β-Component (NAC) Aggregation

Parkinson`s disease (PD) is characterized by Lewy bodies which their major components are α-synuclein (AS) aggregates. Insulin accesses the cerebrospinal fluid cross the blood brain barrier and regulates brain function. Current and future pharmacological strategies being developed to restore neuronal insulin signaling as a potential strategy for slowing PD. It is known that the “non-amyloid β component” (NAC) domain in AS plays role in AS aggregation. The study of the self-assembly of the NAC domains is crucial in order to understand the molecular mechanisms of AS aggregation. Recently, we presented polymorphic structures of the NAC fibrils (Pollock-Gagolashvili, M.E. & Miller, Y. (2017) DOI: 10.1021/acschemneuro.7b00334). The current study examines the effect of insulin on three polymorphic NAC fibrils (Figure 1). We predicted twelve possible insulin-NAC fibrillary models, in which the interactions between insulin and NAC fibrils are based on homology considerations, i.e., identities and similarities between the amino acids. Using molecular dynamics simulations, we first found that insulin can be attached to the NAC fibrils and the interactions are strong and stable along all the timescale of the simulation. Second, insulin can bind in various domains in NAC fibrils. Finally, Insulin does not affect the secondary structure of the NAC fibrils.

Figure 1: Polymorphic NAC oligomers structures. (a) based on Raz & Miller model (Atsmon-Raz, Y. & Miller, Y. J. Phys. Chem. B 119, 10005 (2015)) (b) based on Rienstra`s group (Tuttle, M. D. et al. Nat. Struct. Mol. Biol. 23, 409 (2016)). (c) based on Nussinov’s group (Xu, L., Nussinov, R. & Ma, B. Eur. J. Med. Chem. 121, 841 (2016)).