(477f) Modeling and Simulations of Complex Fibrillar Assemblies and Co-Assemblies Involving Musashi-1, Tau, and SERBP1

The study and understanding of amyloid aggregation and cross-aggregation, where different proteins cross-interact, are key to understanding neurodegenerative diseases such as Alzheimer's disease (AD), where the formation of toxic aggregates of assemblies and co-assemblies can impact several biological pathways and disrupt neuronal function. The formation of assemblies or co-assemblies by such proteins in AD and neurodegenerative diseases is complex and difficult to investigate using experimental methods alone, as it involves the formation of large protein assemblies which may also cross-interact with other assemblies, leading to co-assemblies. In AD, Musashi proteins, which are RNA binding proteins, were found to co-localize and co-aggregate with toxic tau oligomers, both in vitro and in human brains; this interaction may contribute to tau aggregation and the formation of cellular aggresomes, potentially leading to neurodegeneration ¹ . Also, SERBP1, an additional RNA-binding protein, is present in pathological stress granules and tau aggregates in AD, suggesting a potential role in the disease's progression ² . In this study, we use novel in-house molecular dynamics-based approaches to model, simulate, and delineate the formation of large complex assemblies formed by Musashi 1 proteins, and subsequently, we use these to further detail the formation of complex co-assemblies formed by Musashi 1 with tau. Additionally, we use similar in-house computational approaches to uncover the formation of tau aggregates in complex with SERBP1. Our in-house approaches comprise of two stage sets of simulations, in the first of which we use modified energy functions to model and refine the assemblies and co- assemblies, while the second stage we use atomistic all-atom simulations to validate and investigate the structural and physicochemical properties of the complexes. Our presentation will present an in-detail biophysical analysis of the complex assemblies and co-assemblies formed, and provide insights from experimental studies.

1. Montalbano M, McAllen S, Puangmalai N, Sengupta U, Bhatt N, Johnson OD, Kharas MG, Kayed R. RNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction. Nat Commun. 2020 Aug 27;11(1):4305.
2. Breunig K, Lei X, Montalbano M, Guardia GDA, Ostadrahimi S, Alers V, Kosti A, Chiou J, Klein N, Vinarov C, Wang L, Li M, Song W, Kraus WL, Libich DS, Tiziani S, Weintraub ST, Galante PAF, Penalva LOF. SERBP1 interacts with PARP1 and is present in PARylation-dependent protein complexes regulating splicing, cell division, and ribosome biogenesis. eLife 2024; 13:RP98152.