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Grenoble Institut des Neurosciences Grenoble Institut des Neurosciences

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Page personnelle de Marie-Jo Moutin

Membre de

GIN - Équipe "Neuropathologies et dysfonctionnements synaptiques"

Informations de contact

Bureau principal

Bureau principal
2/056
Tél. 
04 56 52 05 44

Thèmes de recherche et activités

Deciphering physiopathological importance of a unique tubulin modification: detyrosination, from enzymes to brain.

     Microtubules are constituents of the cellular skeleton built from dimers of α/β tubulin. They form a dynamic network crucial for cell morphology, mobility and division, and organize intracellular space by allowing trafficking of many organelles and molecules. In neurons, tubulin is very heterogeneous and undergoes various post-translational modifications. We are interested in a particular modification of tubulin, the detyrosination/re-tyrosination cycle. This cycle involves several enzymes (see figure below).



The detyrosination/re-tyrosination cycle. The C-terminal tyrosine residue (Y) of α-tubulin is successively cleaved by carboxypeptidases (TCP) and replaced by a ligase (TTL). This cycle is vital: the absence of TTL causes brain disorganization and newborn animals are dying.


It is a cycle involving several enzymes (see figure above). Although described for more than 40 years this cycle remained incomplete for a long time, only TTL having been identified. In 2017, by an original biochemical approach, we discovered that vasohibins (VASH1/2) in complex with the small protein SVBP are TCPs. This discovery, corroborated by a competing team using a genetic method, is major in the field of cytoskeleton. It now allows a better understanding of the detyrosination/re-tyrosination cycle of tubulin, whose deregulations have been associated with cerebral and cardiac disorders, and with some cancers.

Recently, we have clarified the structural aspects of the enzymatic activity of the vasohibin-SVBP complex in collaboration with Swiss and Chinese crystallographic teams. We have shown the relevance of the detyrosination process for the development of neurons. We revealed that the absence of SVBP (the small chaperone and activator protein of detyrosination enzymes), by strongly altering brain tubulin tyrosination and neuronal physiology, causes brain morphological defects and cognitive impairment in mice and humans. We have shown, with geneticists from Oxford University, that subjects affected by a homozygous mutation in SVBP show microcephaly, intellectual disability, and delays in motor and speech development.


Our work has thus revealed the importance of the cycle and its enzymes for brain physiology. We are now seeking to better understand their role in the neuronal synaptic plasticity that underlies the adaptive capacities of the brain and contributes to memory and learning processes. We are studying the biological mechanisms that link the detyrosination/re-tyrosination cycle, microtubule dynamics and synaptic functions.

A dynamic microtubule penetrates a dendritic spine. Airyscan confocal microscopy showing a microtubule labeled at its tip with an EB3 protein (green) that engages a dendritic spine (red) of a mature cerebral hippocampal neuron. The dotted arrow shows the end of the microtubule at the entrance to the spine (at t = 0), the solid arrow shows its location after 10 and 20 s. The dynamics of microtubules are analyzed in kymographs (distance traveled as a function of time). These experiments, carried out with neurons of various genotypes (TTL / TCP deficient), will make it possible to assess the impact of the tyrosination/re-tyrosination cycle on the dynamics of microtubules in dendritic spines and therefore for the synapse. @L. Peris

    We are also developing an in-depth molecular study of the functioning and regulations of the VASH-SVBP enzyme complex.

Single VASH1 molecules interact with a microtubule. (top) Diagram showing enzymes (green) and a microtubule (gray). (bottom) Representative kymograph obtained by TIRF (Total Internal Reflection Fluorescence) microcopy showing single molecules of VASH1 (at a concentration of 50 pM) fused to the fluorescent protein sfGFP which bind to a microtubule stabilized by taxol. This type of graph makes it possible to analyze the binding kinetics of enzymes, or mutants of interest, on microtubules. @ S. Ramirez-Rios

Having recently revealed an altered detyrosination/re-tyrosination cycle in brains of patients with Alzheimer's disease, this basic research program is also guiding a new therapeutic concept targeting VASH-SVBP complexes to improve the functioning of deficient synapses.

On the other hand, in collaboration with heart physiologists, we are exploring the role of the detyrosination/re-tyrosination cycle in cardiomyocytes and during heart failure.


Contributing people

Marie-Jo Moutin, CNRS research director, responsible
Leticia Peris, Inserm researcher
Yves Goldberg, CEA research director
Jean-Marc Soleilhac, Inserm Ingeneer
Sacnicte Ramirez-Rios, post-doctoral fellow
Chadni Sanyal, PhD student
Isabelle Jacquier, Technician
Aditi Sharma, Master 2


Recent publications

Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease.
L Peris, J Parato, X Qu, JM Soleilhac, F Lanté, A Kumar, ME Pero, J Martínez-Hernández, C Corrao, G Falivelli, F Payet, S Gory-Fauré, C Bosc, MB Ramírez, A Sproul, J Brocard, B Di Cara, P Delagrange, A Buisson, Y Goldberg, MJ Moutin, F Bartolini, A Andrieux.
Brain 2022. https://doi.org/10.1093/brain/awab436.

Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice.
Pagnamenta AT, Heemeryck P, Martin HC, Bosc C, Peris L, Uszynski I, Gory-Fauré S, Couly S, Deshpande C, Siddiqui A, Elmonairy AA, Jayawant S, Murthy S, Walker I, Loong L, Bauer P, Vossier F, Denarier E, Maurice T, Barbier EL, Deloulme JC, Taylor JC, Blair EM, Andrieux A, Moutin MJ.
Hum Mol Genet. 2019 Oct 15;28(20):3391-3405. doi: 10.1093/hmg/ddz186.

Structural basis of tubulin detyrosination by the vasohibin-SVBP enzyme complex.
Wang N, Bosc C, Ryul Choi S, Boulan B, Peris L, Olieric N, Bao H, Krichen F, Chen L, Andrieux A, Olieric V, Moutin MJ, Steinmetz MO, Huang H.
Nat Struct Mol Biol. 2019 Jul;26(7):571-582. doi: 10.1038/s41594-019-0241-y

Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation.
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 Dec 15;358(6369):1448-1453. doi: 10.1126/science.aao4165

Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.
Schuldt M, Pei J, Harakalova M, Dorsch LM, Schlossarek S, Mokry M, Knol JC, Pham TV, Schelfhorst T, Piersma SR, Dos Remedios C, Dalinghaus M, Michels M, Asselbergs FW, Moutin MJ, Carrier L, Jimenez CR, van der Velden J, Kuster DWD.
Circ Heart Fail. 2021 Jan;14(1):e007022. doi: 10.1161/CIRCHEARTFAILURE.120.007022.

Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes.
Chen CY, Salomon AK, Caporizzo MA, Curry S, Kelly NA, Bedi K, Bogush AI, Krämer E, Schlossarek S, Janiak P, Moutin MJ, Carrier L, Margulies KB, Prosser BL.
Circ Res. 2020 Jul 3;127(2):e14-e27. doi: 10.1161/CIRCRESAHA.119.315947.


Recent reviews

The detyrosination/re-tyrosination cycle of tubulin and its role and dysfunction in neurons and cardiomyocytes.
Sanyal C, Pietsch N, Ramirez Rios S, Peris L, Carrier L, Moutin MJ.
Semin Cell Dev Biol 2021 Dec 16;S1084-9521(21)00314-1. doi: 10.1016/j.semcdb.2021.12.006.  

Tubulin post-translational modifications control neuronal development and functions.
Moutin, M-J., Bosc, C., Peris, L., Andrieux, A.
Dev Neurobiol. 2021 Apr;81(3):253-272. doi: 10.1002/dneu.22774.
 

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