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Mechanisms of microtubules stabilization: role of nucleotide bound to tubulin and activity of microtubule associated proteins

on the September 8, 2021
1:30 PM

Thesis defense of Nassiba BAGDADI

On Wednesday, September 8 2021, Nassiba BAGDADI will defend his thesis "Mechanisms of microtubules stabilization: role of nucleotide bound to tubulin and activity of microtubule associated proteins".

This thesis has been directed by Isabelle ARNAL and Virginie STOPPIN-MELLET.

Jury members :

  • Monsieur François DEVRED, INP Marseille - Rewiever
  • Monsieur Christian POÜS, Pharmacy University Paris-Sud - Rewiever
  • Madame Laurence LAFANECHERE, IAB Grenoble - Examiner
  • Madame Laura SCHAEDEL, Center for Biophysics at Saarland University - Examiner

Abstract :

Microtubules are biological dynamic polymers involved in numerous cellular processes such as cell migration, intracellular transport and cell morphology. They alternate between polymerization and depolymerization phases, a behavior named dynamic instability. In differentiated cells, dynamic microtubules coexist with stable microtubules which exhibit a slow tubulin exchange rate (“turn-over”). These stable microtubules are essential for the maintenance of cell morphology and cellular functions. In pathological conditions, the equilibrium between dynamic and stable microtubules is disturbed, thus altering cellular functions. Today, the molecular bases of microtubule stability are still not fully understood. It is widely accepted that some microtubule associated proteins (MAPs), such as the neuronal protein Tau, stabilize directly the microtubules. However, as for the post-translational modifications of tubulin, MAPs mainly reinforce a pre-existing stability of microtubules.
During my thesis, I studied two stabilization mechanisms of microtubules: one mechanism dependent on a microtubular effector, the neuronal protein Tau, and the other solely dependent on tubulin properties. In the first part of my work, I developed a method to characterize the kinetic parameters of the interaction between Tau and microtubules. To do so, I used cell-free systems reconstituted from purified proteins and TIRF (Total Internal Reflection Fluorescence) microscopy that allows to visualize single fluorescent molecules. This approach will enable to study how modifications of Tau modulate its interaction with microtubules and thus its capacity to regulate microtubule stabilization. In the second part of my thesis, I have shown that tubulin associated to GDP can assemble into microtubules, contrary to general dogma stipulating that microtubules can only polymerize from tubulin associated to GTP. These new species of microtubules have unique properties, never described before. Indeed, they are devoid of dynamic instability and are highly stable. Moreover, they polymerize preferentially from the microtubule (–) end which usually is the least active end when microtubules are assembled from GTP-tubulin. Furthermore, I have demonstrated that stable GDP-tubulin islands can stop microtubule depolymerization. Some cellular effectors such as the neuronal proteins Tau and DCX promote GDP-tubulin assembly. Other effectors such as spastin and the kinesin MCAK enable to recycle microtubules assembled from GDP-tubulin, but less efficiently than the ones assembled from GTP-tubulin. Better understanding of this new type of stabilization involving the nucleotide bound to the tubulin during its polymerization could provide leads for the development of new strategies for restoration and/or preservation of stable microtubules in pathologies.

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