Membranes interactions of Aggregation-Prone Proteins and Their Relationship to Liquid-Liquid Phase Separation

Research into the biophysical and molecular interactions between aggregation-prone proteins and cellular membranes is a dynamic and expanding field, given the association of these processes with neurodegenerative diseases. Proteins such as Tau, α-synuclein, TDP-43, and FUS are central to conditions such as Alzheimer’s, Parkinson’s, and ALS; mounting evidence points to their capacity to associate with membranes via electrostatic forces, amphipathic segments, or specific lipid recognition, affecting their structural behavior and assembly. While such interfaces can direct protein conformation and assembly, the complexity of these interactions poses ongoing questions regarding their influence on liquid-liquid phase separation (LLPS), pathological aggregation, and disease progression. Recent studies highlight that membranes are not inert backdrops but dynamic regulators of protein assembly, contributing to the stability or destabilization of protein condensates and their conversion into pathological aggregates. However, despite advances in in vitro and in vivo models, key challenges persist. These include deconvoluting the contributions of different membrane components, understanding the context-dependent nature of protein-membrane interactions, and critically assessing methods and interpretations in the field. There remains a pressing need to compare molecular evidence across systems, to identify unifying principles, and to clarify the mechanistic links between membrane binding, phase behavior, and disease-related aggregation.This Research Topic aims to establish a critical and comparative perspective on how the interaction between aggregation-prone proteins and membranes governs phase separation and aggregation outcomes. The goal is to clarify the molecular underpinnings and context dependencies of these phenomena, encourage mechanistic and cross-system approaches, and spotlight unresolved questions. We seek to challenge interpretations, foster discourse around experimental and methodological limitations, and encourage submissions that emphasize conceptual advances over integrative or comprehensive models.To gather further insights in membrane-associated phase separation and aggregation, we welcome articles that interrogate the molecular basis, comparative features, and experimental limitations within this area. Submissions may address, but are not limited to, the following themes:- Molecular determinants of protein-membrane interactions in aggregation-prone proteins- Effects of membrane surfaces on LLPS, condensate stability, and material properties- Relationship between membrane-associated phase separation behavior and aggregation pathways- Experimental and analytical approaches to study membrane-protein-condensate interfaces in vitro and in cellular models- Conceptual and methodological limitations in interpreting membrane-associated LLPS phenomenaAppendix: We encourage the submission of Original Research, Reviews, Mini Reviews, Hypothesis and Theory papers, and Perspective articles. Topic editors: Josue Juarez, Boopathi Subramanian, Shreyasi Chatterjee Source: https://www.frontiersin.org/research-topics/80243/membranes-interactions-of-aggregation-prone-proteins-and-their-relationship-to-liquid-liquid-phase-separation