Insights into the Mechanistic Perspective Effect of Insulin on the Nonamyloidogenic Component (NAC) and α‑Synuclein Aggregation

Insulin plays important functions in the brain, such as neuroprotective effects on neurons, and it is also involved in cognitive functions (e.g., attention, learning and memory). It is proposed that a lack of insulin in the brain may initiate development of neurodegenerative diseases. Herein, we examined the effect of insulin on aggregates of α-synuclein (AS), a protein that is related to Parkinson’s disease (PD), and its segment nonamyloidogenic component (NAC), which is known to play a crucial role in AS aggregation. The molecular modeling tools assist us to provide insights into the molecular mechanism of the effect of insulin on fibrillation of NAC and AS. Our research leads to three conclusions. First, the preferred interactions between insulin chain B and the “zipper domain” sequence within both NAC and AS appear at the central domain across the fibril axis or at the edge of the fibril. Second, these interactions do not disrupt the cross-β structure of NAC fibril-like oligomers but disrupt the cross-β structure of AS fibril-like oligomers. Thus, insulin does not inhibit the fibrillation of NAC but may inhibit AS fibrillation. Third, some of the polymorphic NAC and AS fibril-like oligomers bind to chain A in insulin. This is the first study that demonstrates that insulin chain A can also participate in the interactions with amyloid fibril-like oligomers. Our study proposes that insulin plays a crucial role in impeding AS aggregation in the brain and consequently could inhibit the development of PD.