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Neurobiology of ionotropic Glutamate receptors in health and disease

imatge Central Grup Recerca

Scientific Team

Researchers
Xavier Altafaj,
Collaborators
Albert Calvente, Paula Sanchis
Technicians
Cristina Grau

Introduction

The iGluRsNeuroLab aims to understand the physiology of NMDA-type ionotropic glutamate receptors (iGluRs) and to unveil the molecular and cellular mechanisms bridging the gap between glutamate receptor dysfunctions and neurological diseases, towards the development of targeted therapeutic approaches. Our efforts are focused to elucidate the molecular mechanisms underlying synaptic plasticity processes in post-synaptic glutamatergic neurons. In particular, we aim to understand the post-translational mechanisms (mainly focusing on phosphorylation events) that regulate iGluRs trafficking and behaviour under physiological conditions and their alterations in neurological disorders. The molecular insights are finally used to design targeted therapeutic approaches and to evaluate their efficacy to attenuate iGluR-mediated neuronal dysfunctions.

 

Methodologically, our experimental strategy starts with the identification of genetic and biochemical alterations of iGluRs in different pathological conditions, both from patients and from animal models. We then evaluate in vitro, the impact of these alterations using cellular models (mouse primary cortical and hippocampal neurons, cell lines). In these models, we study the trafficking of iGluRs towards the plasma membrane, their internalization rate, protein-protein interactions and, in collaboration with electrophysiologists, the potential biophysical changes of altered iGluRs. Further, these findings are translated to mouse models, both to evaluate the physiological relevance of in vitro findings and to develop results-driven therapeutic approaches, along the phenotypic assessment of treated mouse models.



Research lines

The research lines of our emergent lab are focused to study the basic mechanisms of NMDA receptor regulation by phosphorylation and their alterations in physiopathological conditions, as detailed below:

 

1. Study of NMDA receptor trafficking and channel activity regulation by phosphorylation.

 

2. Study of the functional impact of iGluRs de novo mutations in patients with intellectual disability.

 

3. Study of NMDA receptor macromolecular complexes in the early stages of Alzheimer disease.

 

4. Characterization of glutamatergic system alterations in Down syndrome murine models and development of gene therapy strategies.


Grau C., Arató K., Fernández-Fernández J.M., Valderrama A., Sindreu C., Fillat C., Ferrer I., de la Luna S., Altafaj X. "DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors". Front Cell Neurosci. 2014; 8:331.

 

Sindreu C., Bayés A., Altafaj X., Pérez-Clausell, J. "Zinc Transporter-1 Concentrates at the Postsynaptic Density of Hippocampal Synapses". Mol Brain. 2014; 7(1):16.

 

Soto D., Altafaj X., Sindreu C., Bayés À. Glutamate receptor mutations in psychiatric and neurodevelopmental disorders. Commun Integr Biol. 2014; 7(1):e27887.

 

Altafaj, X*., Martín, E., Ortiz-Abalia, J., Valderrama, A., Lao-Peregrin, C., Dierssen, M., Fillat, C. "Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome". Neurobiol Dis. 2013; 52: 117-27.

 

Fillat, C., Altafaj, X. "Gene therapy for Down syndrome". Prog Brain Res. 2012; 197: 237-47.

 

Couchoux H., Bichraoui H., Chouabe C., Altafaj X., Bonvallet R., Allard B., Ronjat M., Berthier C. Caveolin-3 is a direct molecular partner of the Ca(v)1.1 subunit of the skeletal muscle L-type calcium channel. Int J Biochem Cell Biol. 2011; 6 (3): e17998.

 

Fillat C., Dierssen M., Martínez de Lagrán M., Altafaj X. Insights from mouse models to understand neurodegeneration in Down syndrome. CNS Neurol Disord Drug Targets. 2010; 9 (4): 429-38.

 

Ortiz-Abalia J., Sahún I., Altafaj X., Andreu, N., Estivill, X., Dierssen, M., Fillat, C. Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of Down syndrome. Am J Hum Genet. 2008; 83 (4): 479-88.

 

Altafaj X., Ortiz-Abalia J., Fernández M., Potier M.C., Laffaire J., Dierssen M., González-García C., Ceña V., Martí E., Fillat C. Increased NR2A expression and prolonged decay of NMDA-induced calcium transient in cerebellum of TgDyrk1A mice, a mouse model of Down syndrome. Neurobiol Dis. 2008 Dec; 32 (3): 377-84.

 

Altafaj X, France J, Almassy J, Jona I, Rossi D, Sorrentino V, Mabrouk K, De Waard M, Ronjat M. Maurocalcine interacts with the cardiac ryanodine receptor without inducing channel modification. Biochem J. 2007 Sep 1; 406 (2): 309-15.

 

Alvarez M, Altafaj X, Aranda S, de la Luna S. DYRK1A Autophosphorylation on Serine Residue 520 Modulates Its Kinase Activity via 14-3-3 Binding. Mol Biol Cell. 2007 Apr; 18 (4): 1167-78.

 

Altafaj X, Joux N, Ronjat M, De Waard M. Oocyte expression with injection of purified T7 RNA polymerase. Methods Mol Biol. 2006; 322: 55-67. Review.

 

Anderson AA, Altafaj X, Zheng Z, Wang ZM, Delbono O, Ronjat M, Treves S, Zorzato F. The junctional SR protein JP-45 affects the functional expression of the voltage-dependent Ca2+ channel Cav1.1. J Cell Sci. 2006 May 15; 119(Pt 10): 2145-55.

 

Cheng W, Altafaj X, Ronjat M, Coronado R. Interaction between the dihydropyridine receptor Ca2+ channel beta-subunit and ryanodine receptor type 1 strengthens excitation-contraction coupling. Proc Natl Acad Sci U S A. 2005 Dec 27; 102(52): 19225-30.

 

Bouron A, Altafaj X, Boisseau S, De Waard M. A store-operated Ca2+ influx activated in response to the depletion of thapsigargin-sensitive Ca2+ stores is developmentally regulated in embryonic cortical neurons from mice. Brain Res Dev Brain Res. 2005 Sep 8; 159(1): 64-71.

 

Esteve E, Mabrouk K, Dupuis A, Smida-Rezgui S, Altafaj X, Grunwald D, Platel JC, Andreotti N, Marty I, Sabatier JM, Ronjat M, De Waard M. Transduction of the scorpion toxin maurocalcine into cells. Evidence that the toxin crosses the plasma membrane. J Biol Chem. 2005 Apr 1; 280(13): 12833-9.

 

Altafaj X, Cheng W, Esteve E, Urbani J, Grunwald D, Sabatier JM, Coronado R, De Waard M, Ronjat M. Maurocalcine and domain A of the II-III loop of the dihydropyridine receptor Cav 1.1 subunit share common binding sites on the skeletal ryanodine receptor. J Biol Chem. 2005 Feb 11; 280(6): 4013-6.

 

Sandoz G, Lopez-Gonzalez I, Grunwald D, Bichet D, Altafaj X, Weiss N, Ronjat M, Dupuis A, De Waard M. Cavbeta-subunit displacement is a key step to induce the reluctant state of P/Q calcium channels by direct G protein regulation. Proc Natl Acad Sci U S A. 2004 Apr 20; 101(16):6267-72.

 

Martinez de Lagran M, Altafaj X, Gallego X, Marti E, Estivill X, Sahun I, Fillat C, Dierssen M. Motor phenotypic alterations in TgDyrk1a transgenic mice implicate DYRK1A in Down syndrome motor dysfunction. Neurobiol Dis. 2004 Feb; 15(1): 132-42.

 

Esteve E, Smida-Rezgui S, Sarkozi S, Szegedi C, Regaya I, Chen L, Altafaj X, Rochat H, Allen P, Pessah IN, Marty I, Sabatier JM, Jona I, De Waard M, Ronjat M. Critical amino acid residues determine the binding affinity and the Ca2+ release efficacy of maurocalcine in skeletal muscle cells. J Biol Chem. 2003 Sep 26; 278(39): 37822-31.

 

Marti E, Altafaj X, Dierssen M, de la Luna S, Fotaki V, Alvarez M, Perez-Riba M, Ferrer I, Estivill X. Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system. Brain Res. 2003 Feb 28; 964(2): 250-63.

 

Dierssen M, Marti E, Pucharcos C, Fotaki V, Altafaj X, Casas K, Solans A, Arbones ML, Fillat C, Estivill X. Functional genomics of Down syndrome: a multidisciplinary approach. J Neural Transm Suppl. 2001; (61):131-48.

 

Altafaj X, Dierssen M, Baamonde C, Marti E, Visa J, Guimera J, Oset M, Gonzalez JR, Florez J, Fillat C, Estivill X. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum Mol Genet. 2001 Sep 1; 10(18):1915-23.

 

Leder S, Weber Y, Altafaj X, Estivill X, Joost HG, Becker W. Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases. Biochem Biophys Res Commun. 1999 Jan 19; 254(2):474-9.

imatge personal
 

Subgroup head (PI)

Xavier Altafaj
Telephone  
+34 932607215
E-mail  
xaltafaj@idibell.cat
 
© 2017 Institut d'Investigació Biomèdica de Bellvitge



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