2025 AIChE Annual Meeting

Computational Studies on the Cross-Interactions between ?-Synuclein/Amyloid-? and ?-Synuclein/Tau

Amyloid-beta plaques, tau neurofibrillary tangles, and alpha-synuclein-rich Lewy bodies are pathological hallmarks of Alzheimer's and Parkinson’s diseases, and are strongly associated with protein misfolding and aggregation [1,2]. Cross-interactions between alpha-synuclein and tau have been shown to promote mutual aggregation, potentially accelerating tau tangle formation and contributing to Alzheimer's disease pathology [1]. Similarly, alpha-synuclein has been reported to interact with amyloid-beta, facilitating the formation of amyloid plaques and Lewy bodies observed in both Alzheimer’s and Parkinson's diseases [2]. In this study, we introduced a novel computational approach of our lab [3] to investigate alpha-synuclein cross-interactions with tau and amyloid-beta. Particularly, we used biased molecular dynamics simulations under constraints mimicking and enhancing cross-interactions, followed by conventional molecular dynamics simulations to investigate amyloid cross-interactions of alpha-synuclein with amyloid-beta and tau, individually. Our studies highlight the importance of polymorphism in amyloid cross-interactions and suggest potential axial-stacking cross-interactions that alpha-synuclein can form with amyloid-beta and tau. We observe the formation of regions of high shape complementarity and amyloid steric zippers in the derived cross-interacting conformations. The interactions stabilizing the cross-interactions are analyzed in-detail, uncovering which residue-domains could be critical for cross-interactions. Understanding the structural basis of these interactions is crucial for delineating the mechanisms of these cross-interactions in neurodegenerative diseases.

1. Hojjatian A, Dasari AKR, Sengupta U, et al. tau induces formation of α-synuclein filaments with distinct molecular conformations. Biochem Biophys Res Commun. 2021;554:145-150.

2. Ono K, Takahashi R, Ikeda T, Yamada M. Cross-seeding effects of amyloid β-protein and α-synuclein. J Neurochem. 2012;122(5):883-890.

3. Xenophontos X, Vlachou A, Hunt RK, Tamamis P. Amyloid Cross-Interactions through the Lens of Simulations: The case of Aβ-IAPP (paper under review).