Skip to Main content Skip to Navigation
Theses

Impact de tau et ses formes pathologiques sur l'organisation des réseaux microtubulaires

Abstract : Microtubules are key components of the eukaryotic cytoskeleton and are involved in major cellular events. They undergo constant remodeling through alternative cycles of growth and shrinkage of their extremities, a behavior known as dynamic instability. Microtubules are particularly abundant in neurons; they are organized into bundles within axons and dendrites to maintain the polarized shape of these highly specialized cells and to allow cargo transport. Numerous factors regulate the plasticity of the microtubule network in neurons. Among them, tau is a neuro-specific microtubule-associated protein (MAP). Tau is a major microtubule bundler also known to stabilize microtubules by promoting their growth and inhibiting their shrinkage. Although the interaction of tau with microtubules has been widely studied, the mechanisms by which this protein controls the spatial organization of microtubules remain elusive. To address this question, we reconstitute in vitro microtubule self-organization in presence of various tau isoforms, fragments and mutants. We find that the ability of tau to induce stable microtubule bundles depends on two conserved hexapeptides in tau’s microtubule-binding domain and is modulated by tau’s projection domain. Furthermore, our data demonstrate that site-specific phosphorylation of tau inhibits either microtubule bundling or stabilization generating alternative networks composed of stable single or dynamic bundled microtubules. We also show that some disease-related mutations closed to the hexapeptides strikingly enhance the capacity of tau to form bundles of highly dynamic microtubules. Finally, cryo-EM experiments indicate that tau proteins induce microtubule lattice defects known to soften microtubules, a primary structural change allowing microtubule-bending deformation during bundling. Overall, our results highlight novel phospho-dependent mechanisms by which tau regulates microtubule network organization. This work also reveals how abnormal modifications of tau, such as abnormal phosphorylation or mutations found in Alzheimer’s disease and related dementia, might alter cytoskeleton organization during neurodegeneration.
Complete list of metadatas

Cited literature [444 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-01899900
Contributor : Abes Star :  Contact
Submitted on : Wednesday, November 28, 2018 - 11:07:20 AM
Last modification on : Friday, October 23, 2020 - 5:04:19 PM

File

PREZEL_2017_archivage.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-01899900, version 2

Collections

STAR | UGA

Citation

Eléa Prezel. Impact de tau et ses formes pathologiques sur l'organisation des réseaux microtubulaires. Neurosciences [q-bio.NC]. Université Grenoble Alpes, 2017. Français. ⟨NNT : 2017GREAV044⟩. ⟨tel-01899900v2⟩

Share

Metrics

Record views

130

Files downloads

151