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Grenoble Institut des Neurosciences Grenoble Institut des Neurosciences

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Microtubules of the synaptic compartment

Objectifs

The objective of the project is to better understand, the role of a unique modification of microtubules, called the detyrosination/tyrosination cycle for neurons synapses. Different animal models in which microtubules composition is altered will be used.
 

Résumé

Microtubules, which are composed of ?/?-tubulin heterodimers, form a dynamic network involved in several cellular processes including synaptic maturation. Microtubule dynamics is regulated by proteins which association to microtubules is modulated by post-translational modifications of tubulin, including the detyrosination/re-tyrosination cycle. In this cycle, the C-terminal tyrosine of ?-tubulin is removed by carboxypeptidases (TCPs) and re-added by a ligase (TTL). Our group demonstrated that tyrosinated-tubulin is vital by analyzing the TTL KO mouse showing deleterious brain disorganization. We also recently identified TCP enzymes (VASH-SVBP) that remained elusive for 40 years and developed the KO mice. SVBP-null brains show brain abnormalities with microcephaly and cognitive deficit.
In this project, the student will prepare synaptosomes from wild type and transgenic mice (TTL and r TCPs mice) to analyze the presence of modified ?-tubulin (tyrosinated, detyrosinated) and of specific molecular partners in the pre- and post-synaptic compartments. He/her will analyze the distribution of modified microtubules and partners in the axon, dendrites and dendritic spines of mature neurons in culture. In a next step, depending on the results obtained, he/her will perform rescue experiments by the expression of wild type or mutated versions of TTL or TCPs in the mature KO neurons.
 

Méthodes

Techniques used will include cellular biology (primary neuronal cultures, neuron transfection, virus infection, immunofluorescence and confocal microscopy) and biochemistry (brain dissection, subcellular fractionation, western-blot analysis).
 

Références

  • Peris L, Bisbal M, Martinez-Hernandez J, Saoudi Y, Jonckheere J, Rolland M, Sebastien M, Brocard J, Denarier E, Bosc C, Guerin C, Gory-Fauré S, Deloulme JC, Lanté F, Arnal I, Buisson A, Goldberg Y, Blanchoin L, Delphin C, Andrieux A. Nat Commun. 2018 Sep 17;9(1):3775. doi: 10.1038/s41467-018-05869-z. PMID: 30224655 A key function for microtubule-associated-protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines.
  • Aillaud C, Bosc C, Peris L, Bosson A, Heemeryck P, Van Dijk J, Le Friec J, Boulan B, Vossier F, Sanman LE, Syed S, Amara N, Couté Y, Lafanechère L, Denarier E, Delphin C, Pelletier L, Humbert S, Bogyo M, Andrieux A, Rogowski K, Moutin MJ. Science. 2017 Nov 16. pii: eaao4165. doi: 10.1126/science.aao4165. Vasohibins/SVBP are tubulin carboxypeptidases (TCP) that regulate neuron differentiation.
  • Wang N, Bosc c, Ryul Choi S, Boulan B, Peris L, Olieric N, Bao N, Krichen F, Chen L, Andrieux A, Olieric V, Moutin MJ, Steinmetz M, Huang H. Nature Structural & Molecular Biology 2019 (In press) Structural basis of tubulin detyrosination by vasohibin-SVBP enzyme complex and functional implications.

Domaines d'expertise requis

Cell biology, neurobiology, microscopy, biochemistry

Contacts

L. Peris, CR Inserm
Email : leticia.peris@univ-grenoble-alpes.fr
Tél : 0456520535
 

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Mise à jour le 26 juin 2020

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