Close

Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

Ruensern Tan, Aileen J. Lam, Tracy Tan, Jisoo Han, Dan W. Nowakowski, Michael Vershinin, Sergi Simo, Kassandra M. Ori-McKenney, Richard J. McKenney

Preprint posted on 22 September 2018 https://www.biorxiv.org/content/early/2018/09/22/423376

Article now published in Nature Cell Biology at http://dx.doi.org/10.1038/s41556-019-0375-5

and

Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes

Valerie Siahaan, Jochen Krattenmacher, Amayra Hernandez-Vega, Anthony A Hyman, Stefan Diez, Zdenek Lansky, Marcus Braun

Preprint posted on 22 September 2018 https://www.biorxiv.org/content/early/2018/09/22/424374

Article now published in Nature Cell Biology at http://dx.doi.org/10.1038/s41556-019-0374-6

Islands on the highways! The microtubule-associated protein tau forms reversible islands on microtubules in vitro and modulates the behavior of motor proteins and severing enzymes.

Selected by Satish Bodakuntla

Context: Ever since the discovery of microtubule-associated proteins (MAPs) in the 1970s, tau has received particular interest as it is involved in a number of neurodegenerative diseases and undergoes diverse molecular behaviours (tau aggregation and tau phase separation droplets). While tau was shown to regulate microtubule interactions of several MAPs including motor proteins and severing enzymes, the underlying mechanisms remained largely elusive. In these preprints, the authors show that tau forms reversible condensates on the microtubules in vitro and reveal how these condensates regulate the microtubule interaction of severing enzymes and molecular motors.

Key findings: The authors used in vitro reconstitution assays and observed that tau binds microtubules in a non-homogenous manner, i.e. some regions of microtubules are densely decorated with tau molecules, termed ‘tau condensates’ or ‘tau islands’. These condensates can grow and shrink along the microtubule, merge with the nearby condensates and are reversible upon removal of tau from the solution. Consistent with earlier in vivo data showing that tau prevents microtubule severing, the authors observed that tau islands efficiently protect the microtubules from katanin and spastin mediated-severing. Interestingly, these tau islands selectively form barriers on microtubules to regulate the movement of molecular motors. While highly processive molecular motors, like dynein and kinesin-8 could efficiently pass through the condensates, kinesin-1 motors could not penetrate the tau islands. Overall, the authors present a novel idea that tau condensation is in fact a physiological form of tau self-association and thereby explain the physiological importance of tau oligomerization in mediating its functions.

Why this preprint is interesting: Microtubules, formed by well-conserved tubulin heterodimers, must functionally specialize to perform a plethora of diverse functions, which many times is attained by interacting with several MAPs. Strikingly, in these preprints, the authors go one step ahead and show how an individual MAP – tau – by forming two distinct phases spatially confers different properties to microtubules. Further, the observations made by the authors raise very intriguing questions for the microtubule community.

Questions the work raises: The preprints complement each other well to strengthen their hypothesis and to address possible questions in the scope of their study. That said, their results raise intriguing questions for the follow-up studies.

  1. Why do tau condensates form islands specifically in some regions of microtubules?
  2. Why does tau form condensates only on taxol-stabilised microtubules and not on GMP-CPP microtubules?
  3. Can other microtubule-associated proteins also form condensates or islands?

Tags: microtubule-associated proteins, microtubules, molecular motors, tau

Posted on: 12 December 2018 , updated on: 19 December 2018

doi: https://doi.org/10.1242/prelights.6267

(No Ratings Yet)

Author's response

Richard J. McKenney shared about Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

We appreciate the author’s interest in our work! We are especially excited by the finding that self-association of tau molecules, long thought to be a disease-specific event, may also be relevant to the physiological functions of tau molecules in cells. Our work reveals a novel, reversible form of tau self-association that appears distinct from the pathological aggregation typically observed in tauopathies. We hope this discovery opens up new avenues of thought and research about both the physiological and pathological states of the tau molecule in neurons.

In regards to the author’s excellent questions:

  1. Why do tau condensates form islands specifically in some regions of microtubules?

This is the most pressing question in our minds! We observed that, remarkably, tau condensates consistently appear at specific “hot-spots” on the microtubule lattice. We have hypothesized that these spots could reflect local changes in microtubule architecture or even damage to the lattice. The first idea is supported by other data in the paper showing that tau condensation is sensitive to both the nucleotide state and curvature of the microtubule lattice. Current experiments in the lab are focused on answering this question.

  1. Why does tau form condensates only on taxol-stabilised microtubules and not on GMP-CPP microtubules?

Previous studies have suggested that tau behaves differently on GDP (facilitated by taxol in our experiments) versus GTP (mimicked by GMP-CPP) lattice architectures (Duan et al. JMB 2017, McVicker et al. JBC 2011). Our results build on these observations by directly visualizing the behavior of tau molecules on these two types of lattices. Surprisingly, we observed that tau condensation only occurs on the GDP (taxol) form of the lattice, suggesting that a change in lattice architecture is necessary to facilitate, or “gate” tau condensation. Recent high-resolution cryo-EM structures of GDP versus GTP microtubule lattices have revealed that the primary difference in lattice architecture lies in the inter-tubulin dimer distance (Zhang et al. PNAS, 2018). Thus we hypothesize that tau condensation is likely regulated by the spacing of the inter-dimer distance within the lattice. Biologically, this implies that tau condensation is spatially regulated away from the growing plus-ends of microtubules, which retain a GTP-tubulin cap, and possibly away from newly incorporated GTP-tubulin dimers along the lattice (Vemu et al. Science. 2018).

  1. Can other microtubule-associated proteins also form condensates or islands?

This is an excellent question! There are hints of similar behavior in recent studies (Monroy et al. Nat. Commun. 2018), but a comprehensive analysis of how all MAPs behave on the microtubule lattice, both alone and in combination with other MAPs, is currently lacking. Single molecule imaging will be an excellent technique to answer this question in the near future, and we fully expect there to be more surprises along the way!

and

Marcus Braun shared about Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes

Starting with our previous finding of tau liquid-liquid phase separation (Hernández-Vega, et al. 2017. “Local Nucleation of Microtubule Bundles Through Tubulin Concentration Into a Condensed Tau Phase.” Cell Reports 20 (10): 2304–12.), which demonstrated that the intrinsically disordered tau molecules can interact to form liquid drops of high-density tau, we wondered if the presence of pre-assembled microtubules could facilitate tau-tau interaction. We reasoned that individual tau proteins could interact more readily with each other when being tethered to the microtubule via their binding domains. During their diffusive exploration of the microtubule surface, we thought, the tau molecules, might bump into each other a lot more often than during 3D diffusion in solution. To our delight, we indeed found that the reduction in dimensionality from 3D to 2D diffusion resulted in the interaction of diffusive tau molecules leading to the formation of tau islands in absence of any crowding agents, at physiological ionic strengths and at nano-molar concentrations. The islands formed are not liquid (as tau associated with the islands is not diffusing), but rather solid (with the individual tau molecules being stationary), but very dynamic as they reversibly grow and shrink from their edges, depending on the tau concentration in solution. Our finding that these tau islands regulate the accessibility of the microtubule surface for kinesin molecular motors and the microtubule severing enzyme katanin, makes us confident that reversible island formation by intrinsically disordered MAPs will emerge as common means, in particular in the context of neuronal axons, where tau is present in vivo, to regulate microtubule accessibility for molecular motors and other associated proteins, thus governing motorized transport and cytoskeletal dynamics.

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the biochemistry category:

Preprint Peer Review – Biochemistry Course at UFRJ, Brazil

Communication of scientific knowledge has changed dramatically in recent decades and the public perception of scientific discoveries depends on the peer review process of articles published in scientific journals. Preprints are key vehicles for the dissemination of scientific discoveries, but they are still not properly recognized by the scientific community since peer review is very limited. On the other hand, peer review is very heterogeneous and a fundamental aspect to improve it is to train young scientists on how to think critically and how to evaluate scientific knowledge in a professional way. Thus, this course aims to: i) train students on how to perform peer review of scientific manuscripts in a professional manner; ii) develop students' critical thinking; iii) contribute to the appreciation of preprints as important vehicles for the dissemination of scientific knowledge without restrictions; iv) contribute to the development of students' curricula, as their opinions will be published and indexed on the preLights platform. The evaluations will be based on qualitative analyses of the oral presentations of preprints in the field of biochemistry deposited in the bioRxiv server, of the critical reports written by the students, as well as of the participation of the students during the preprints discussions.

 



List by Marcus Oliveira

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf

 



List by Nándor Lipták

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

Also in the cell biology category:

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

preLights peer support – preprints of interest

This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.

 



List by preLights peer support

The Society for Developmental Biology 82nd Annual Meeting

This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.

 



List by Joyce Yu, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.

 



List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Dey Lab, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage
Close