RNA stores tau reversibly in complex coacervates.
Xuemei Zhang,Yanxian Lin,Neil A. Eschmann,Hongjun Zhou,Jennifer N. Rauch,Israel Hernandez,Elmer Guzman,Kenneth S. Kosik,Songi Han +8 more
TLDR
It is reported that tau protein, the primary constituent of Alzheimer neurofibrillary tangles, can form liquid droplets and therefore has the necessary biophysical properties to undergo liquid-liquid phase separation (LLPS) in cells and suggests that the droplet state can incubate tau and predispose the protein toward the formation of insoluble fibrils.Abstract:
Nonmembrane-bound organelles that behave like liquid droplets are widespread among eukaryotic cells. Their dysregulation appears to be a critical step in several neurodegenerative conditions. Here, we report that tau protein, the primary constituent of Alzheimer neurofibrillary tangles, can form liquid droplets and therefore has the necessary biophysical properties to undergo liquid-liquid phase separation (LLPS) in cells. Consonant with the factors that induce LLPS, tau is an intrinsically disordered protein that complexes with RNA to form droplets. Uniquely, the pool of RNAs to which tau binds in living cells are tRNAs. This phase state of tau is held in an approximately 1:1 charge balance across the protein and the nucleic acid constituents, and can thus be maximal at different RNA:tau mass ratios, depending on the biopolymer constituents involved. This feature is characteristic of complex coacervation. We furthermore show that the LLPS process is directly and sensitively tuned by salt concentration and temperature, implying it is modulated by both electrostatic interactions between the involved protein and nucleic acid constituents, as well as net changes in entropy. Despite the high protein concentration within the complex coacervate phase, tau is locally freely tumbling and capable of diffusing through the droplet interior. In fact, tau in the condensed phase state does not reveal any immediate changes in local protein packing, local conformations and local protein dynamics from that of tau in the dilute solution state. In contrast, the population of aggregation-prone tau as induced by the complexation with heparin is accompanied by large changes in local tau conformations and irreversible aggregation. However, prolonged residency within the droplet state eventually results in the emergence of detectable β-sheet structures according to thioflavin-T assay. These findings suggest that the droplet state can incubate tau and predispose the protein toward the formation of insoluble fibrils.read more
Citations
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Protein Phase Separation: A New Phase in Cell Biology.
Steven Boeynaems,Steven Boeynaems,Simon Alberti,Nicolas L. Fawzi,Tanja Mittag,Magdalini Polymenidou,Frederic Rousseau,Frederic Rousseau,Joost Schymkowitz,Joost Schymkowitz,James Shorter,Benjamin Wolozin,Ludo Van Den Bosch,Peter Tompa,Peter Tompa,Monika Fuxreiter +15 more
TL;DR: A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.
Journal ArticleDOI
Tau protein liquid–liquid phase separation can initiate tau aggregation
Susanne Wegmann,Bahareh Eftekharzadeh,Katharina Tepper,Katarzyna Marta Zoltowska,Rachel E. Bennett,Simon Dujardin,Pawel R. Laskowski,Danny MacKenzie,Tarun V. Kamath,Caitlin Commins,Charles R. Vanderburg,Allyson D. Roe,Zhanyun Fan,Amandine Molliex,Amayra Hernández-Vega,Daniel J. Müller,Anthony A. Hyman,Eckhard Mandelkow,Eckhard Mandelkow,J. Paul Taylor,J. Paul Taylor,Bradley T. Hyman +21 more
TL;DR: It is demonstrated that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain, and it is suggested that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.
Journal ArticleDOI
mRNA structure determines specificity of a polyQ-driven phase separation
Erin M Langdon,Yupeng Qiu,Amirhossein Ghanbari Niaki,Grace A. McLaughlin,Chase A. Weidmann,Therese M. Gerbich,Jean A. Smith,John M. Crutchley,Christina M. Termini,Kevin M. Weeks,Sua Myong,Amy S. Gladfelter,Amy S. Gladfelter +12 more
TL;DR: The shape of RNA can promote the formation and coexistence of the diverse array of RNA-rich liquid compartments found in a single cell and support a model in which structure-based, RNA-RNA interactions promote assembly of distinct droplets and protein-driven, conformational dynamics of the RNA maintain this identity.
Journal ArticleDOI
Stress granules and neurodegeneration
Benjamin Wolozin,Pavel Ivanov +1 more
TL;DR: A model describing how intrinsic vulnerabilities within the cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent is suggested, which might accelerate the pathophysiology of many neurodegenerative diseases and myopathies.
Journal ArticleDOI
Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease
Hendrik Wesseling,Waltraud Mair,Mukesh Kumar,Christoph N. Schlaffner,Shaojun Tang,Pieter Beerepoot,Benoit Fatou,Amanda J. Guise,Long Cheng,Shuko Takeda,Jan Muntel,Melissa S. Rotunno,Simon Dujardin,Peter Davies,Kenneth S. Kosik,Bruce L. Miller,Sabina Berretta,John C. Hedreen,Lea T. Grinberg,William W. Seeley,Bradley T. Hyman,Hanno Steen,Judith A. Steen +22 more
TL;DR: Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease, and unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation.
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