Molecular Neurobiology - Universidad Autónoma de Madrid

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Molecular Neurobiology
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Glycine neurotransporters: molecular structure,
biogenesis and regulation
Carmen Aragón Rueda
Function of microtubular proteins in neurons
Jesús Avila de Grado
Neuronal repair and molecular therapy in neurodegeneration.
Spinocerebellar ataxias
Javier Díaz Nido
Molecular basis of neuronal plasticity
F Javier Díez Guerra
Molecular and cellular mechanisms for synaptic plasticity
José Antonio Esteban García
Molecular bases of the glutamatergic synapses:
study of glutamate and glycine transporters
Cecilio Giménez Martín
Huntington’s disease and other CNS disorders
José Lucas Lozano
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Biology of human neural stem cells. Potential for cell and
gene therapy in neurodegeneration
Alberto Martínez Serrano
Calcium signalling in mitochondria and insulin/leptin signalling
during ageing
Jorgina Satrústegui Gil-Delgado
Molecular pathology of Alzheimer’s disease
Fernando Valdivieso Amate
Molecular mechanism of neurodegeneration and regeneration
Francisco Wandosell Jurado
Role of lipids in neuronal physiology and pathology
María Dolores Ledesma Muñoz
Molecular pathways to Neurodegeneration. Cellular and
Animal Models: Role of post-translational modification
of Tau in its degradation by calpains
Félix Hernández
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Molecular Neurobiology
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Glycine neurotransporters: molecular structure, biogenesis and regulation
Research summary
Our group is focused on the study of molecular mechanism, biogenesis, intracellular traffic, regulation and
pharmacology of plasma membrane glycine transporters (GLYT1 and GLYT2) that play a major role in the final
step of glycinergic transmission by removing specifically the neurotransmitter from the synapse. Our aim is to
gain insight in the physiology and pathologies associated to alterations of glycinergic neurotransmission as
neuropathic pain and muscle tone pathologies as hyperekplexia, myoclonus or epilepsia. In humans, mutations
in SLC6A5 gene (GLYT2) are the cause of autosomal sporadic hyperekplexia.
Research summary
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In collaboration with the CBMSO Bioinformatics group (A. Ramírez / A. Morreale) we have generated 3D
models for GLYT1 and GLYT2. Using molecular dynamics simulations and electrostatic calculations of the
transporters in the presence of Na + , we have identified and experimentally confirmed, the residues involved
in the additional Na + site (Na3) of GLYT2 (stoichiometry: 3Na + :1Cl - :1glycine). The replacement of Asp471
located in TM6 of GLYT2, but not the equivalent position in GLYT1 (Asp295, coupled to two Na + ), reduced Na +
affinity and cooperativity of glycine transport. An efficient allosteric communication between Asp471 and the
Na1-2 sites was inferred from the differential Na + -induced responses to tiol reagents by target cysteines in 471
(GLYT2) and 295 (GLYT1). Target cysteines show differential glycine-dependent accessibility in both isoforms.
Na + protected target cysteine from inhibition with reagent at a conformationally restricted temperature in GLYT2
but not in GLYT1, indicating direct binding to position 471.
We studied the traffic of GLYT2, which recycles between endosomes and plasma membrane through
constitutive and regulated pathways. The activation of PKC by phorbol-esters inhibits GLYT2 transport through
an increase of the internalization rate causing net accumulation of the protein in internal compartments and a
redistribution of the transporter from rafts to non-raft domains in the plasma membrane of brainstem primary
neurons and synaptosomes.
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Molecular Neurobiology
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Glycine neurotransporters: molecular structure, biogenesis and regulation
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Figure 1. Molecular models for GLYT1 and GLYT2. Lateral view of the transporter modeled structures showing the isosurfaces of favourable
interaction with Na+ ion (-5 Kcal/mol, red). The proposed region involved in Na+ coordination in Na3 site of GLYT2 is magnified for comparison
with the equivalent area of GLYT1.
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Glycine neurotransporters: molecular structure, biogenesis and regulation
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Figure 2. Immunohistochemistry of rat spinal cord slices (ventral horn) Close apposition in the GLYT2 (red fluorescence) and purinergic receptors
P2Y12 (green fluorescence) distribution.
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Molecular Neurobiology
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Glycine neurotransporters: molecular structure, biogenesis and regulation
Group Leader:
Carmen Aragón Rueda
Scientific Staff:
Beatriz López-Corcuera
Postdoctorals:
Esperanza Jiménez Martínez
Predoctoral Fellows:
Pablo Alonso Torres
Gonzalo Pérez Siles
Jaime de Juan Sanz
Research summary
Staff
Publications
Students:
Esther Arribas
Jennifer Mayordomo
Technical Assistance:
Enrique Núñez Balbuena
Other activities
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Molecular Neurobiology
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Glycine neurotransporters: molecular structure, biogenesis and regulation
Publications
Núñez, E., Alonso-Torres, P., Fornés, A., Aragón, C. and López-Corcuera, B. (2008). The neuronal glycine transporter GLYT2 associates
with membrane rafts: functional modulation by lipid environment. J. Neurochem. 105, 2080-2090.
Fornés, A., Núñez, E., Alonso-Torres, P., Aragón, C. and López-Corcuera, B. (2008).Trafficking properties and activity regulation of the
neuronal glycine transporter GLYT2 by protein kinase C. Biochem. J. 412, 495-506.
Giménez, C., Zafra, F., López-Corcuera, B. and Aragón, C. (2008). Bases moleculares de la hiperplexia hereditaria. Rev. Neurol. 47, 648-652.
Research summary
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Molecular Neurobiology
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Glycine neurotransporters: molecular structure, biogenesis and regulation
Other activities
Participaciones orales por Invitación:
C. Aragón. “Dynamic Properties of Neuronal Glycine Transporter GLYT2”. ESF Conference in Biomedicine. Rare Diseases: Channels
and Transporters. March 2008 (S. Feliú de Guisols, Gerona, Spain)
B. López-Corcuera. “Functional and dynamic properties of glycine neurotransporters”. 6th FENS Forum of European Neuroscience. July
2008 (Geneva, Switzerland).
Pertenencia al Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, grupo U751) del Instituto de Salud Carlos
III desde 2007.
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Staff
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Function of microtubular proteins in neurons
Research summary
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Doctoral theses
Our main objectives are: to understand tau pathology in Alzheimer disease and to look for a therapeutical
use of ensheating olfactory cells as reparators of axonal damage. Tau pathology in those neurodegenerative
disorders is mainly due to its hyperphosphorylation and its aberrant aggregation, and, in the last two years,
we have done some experiments to know how those phosphorylation and aggregation processes take place.
In this way, we have determined a region in tau molecule that plays an important role in those features
(phosphorylation and aggregation). In addition, we have suggested a novel mechanism; in which tau protein
could be involved, to explain the assembly of a pathological protein aggregate found in the brain of Alzheimer
disease patients, the Hirano body. On the other hand, we have continued our analyses on tau phosphorylation
by protein kinase GSK3, we have found, during GSK3 analysis, an activation of this enzyme, after an increase
of intracellular calcium. In a study carried out by F. Hernández, it has been shown that an increase in intracellular
calcium results in the activation of calpain, a protein that cleaves GSK3 removing its aminoterminal region and,
as result of that, the kinase is activated.
Also, we have described that tau protein, in extracellular form, may play a role in the tau pathology propagation,
in Alzheimer disease. Our data suggest that upon neurondegeneration, intracellular tau becomes extracellular
tau, and this extracellular protein can bind to cellular receptors (muscarinic receptors M1 and M3). As a
consequence of that an increase in intracellular calcium could occur. This calcium increase could be toxic for
the cell.
About our studies on ensheating olfactory glia cells as reparators of axonal damage, we have immortalized
these cells and studied their functionally after immortalization and desinmmortalization. These studies are
related to the possible future therapeutical use of these cells.
Awards
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Molecular Neurobiology
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Function of microtubular proteins in neurons
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Figure 1. Atrophy in the dentate gyrus of the hippocampus in GSK-3β-overexpressing transgenic mice can be observed. Representative sagital
section from 18-month-old mice DAPI stained is shown.
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Molecular Neurobiology
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Function of microtubular proteins in neurons
Group Leader:
Jesús Avila de Grado
Scientific Staff:
Félix Hernández Pérez
Filip Lim
María Teresa Moreno-Flores
Francisco José Moreno Muñoz
Mar Pérez Martínez
Laura Sayas Casanova
Technical Assistance:
María Jesús Martín Bermejo
Raquel Cuadros Catalán
Esther García García
Ana Belén García Gómez
Elena Langa Gabriel
Nuria de la Torre Alonso
Research summary
Staff
Publications
Other activities
Doctoral theses
Postdoctoral Fellows:
Vega García-Escudero
Alberto Gómez Ramos
Thorsten Koecheling
Alicia Rubio Garrido
Ismael Santa-María Pérez
Graduate Students:
Almudena Fuster Matanzo
Maite Gallego Hernández
Elena Gómez de Barreda Santiago
Paloma Goñi Oliver
Diana Simón Sanz
Elena Tortosa Binacua
Zahady Velasquez
Awards
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Function of microtubular proteins in neurons
Publications
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Staff
Publications
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Doctoral theses
Awards
Avila, J. (2007). Neuronal disorders: Introduction. Cell. Mol.
Life Sci. 64, 2191-2193.
Avila, J. and Hernandez, F. (2007). GSK-3 inhibitors for
Alzheimer’s disease. Expert. Rev. Neurother. 7, 1527-1533.
Engel, T. et al., (2007). A mouse model to study tau pathology
related with tau phosphorylation and assembly. J. Neurol. Sci.
257, 250-254.
Gomez-Sintes, R. et al., (2007). Neuronal apoptosis and
reversible motor deficit in dominant-negative GSK-3
conditional transgenic mice. Embo J. 26, 2743-2754.
Goni-Oliver, P. et al., (2007). N-terminal cleavage of GSK-3 by
calpain: a new form of GSK-3 regulation. J. Biol. Chem. 282,
22406-22413.
Hernandez, F. and Avila, J. (2007). Tauopathies. Cell. Mol. Life.
Sci. 64, 2219-2233.
Hirotani, S., et al., (2007). Inhibition of glycogen synthase
kinase 3beta during heart failure is protective. Circ. Res. 101,
1164-1174.
Hooper, C. et al., (2007). Glycogen synthase kinase-3
inhibition is integral to long-term potentiation. Eur. J. Neurosci.
25, 81-86.
Kortazar, D. et al., (2007). Role of cofactors B (TBCB) and E
(TBCE) in tubulin heterodimer dissociation. Exp. Cell. Res.
313, 425-436.
Pastrana, E. et al., (2007). BDNF production by olfactory
ensheathing cells contributes to axonal regeneration of
cultured adult CNS neurons. Neurochem. Int. 50, 491-498.
Perez, M. et al., (2007). The role of the VQIVYK peptide in tau
protein phosphorylation. J. Neurochem. 103, 1447-1460.
Rubio, A., Avila, J. and de Lecea, L. (2007). Cortistatin as a
therapeutic target in inflammation. Expert Opin. Ther. Targets
11, 1-9.
Salcedo, M. et al., (2007). The marine sphingolipid-derived
compound ES 285 triggers an atypical cell death pathway.
Apoptosis 12, 395-409.
Santa-Maria, I., et al., (2007). Tramiprosate, a drug of potential
interest for the treatment of Alzheimer’s disease, promotes an
abnormal aggregation of tau. Mol. Neurodegener. 2, 17.
Santa-Maria, I. et al., (2007). Taurine, an inducer for tau
polymerization and a weak inhibitor for amyloid-beta-peptide
aggregation. Neurosci. Lett. 429, 91-94.
Zhu, X. et al., (2007). Treating the lesions, not the disease. Am.
J. Pathol. 170, 1457-1459.
Avila, J. (2008). Tau kinases and phosphatases. J. Cell. Mol.
Med. 12, 258-259.
Avila, J., et al., (2008) Isolation of microtubules and microtubule
proteins. In: Curr. Protoc. Cell. Biol. John Wiley & Sons. pp
Unit 3 29
Bjorkdahl, C., et al., (2008). Small heat shock proteins Hsp27 or
alphaB-crystallin and the protein components of neurofibrillary
tangles: tau and neurofilaments. J. Neurosci. Res. 86, 1343-
1352.
Engel, T. et al., J. (2008). Lithium, a potential protective drug in
Alzheimer’s disease. Neurodegener. Dis. 5, 247-249.
Engel, T. et al., (2008). Hippocampal neuronal subpopulations
are differentially affected in double transgenic mice
overexpressing frontotemporal dementia and
parkinsonism linked to chromosome 17 tau and glycogen
synthase kinase-3beta. Neuroscience 157, 772-780.
Gomez-Ramos, A. et al., (2008). Extracellular tau promotes
intracellular calcium increase through M1 and M3 muscarinic
receptors in neuronal cells. Mol. Cell. Neurosci. 37, 673-681.
Guerrero, R. et al., (2008). Park2-null/tau transgenic mice
reveal a functional relationship between parkin and tau.
J. Alzheimers Dis. 13, 161-172.
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Doctoral theses
Awards
Publications
Hernandez, F. and Avila, J. (2008). Tau aggregates and tau
pathology. J. Alzheimers Dis. 14, 449-452.
Hernandez, F. and Avila, J. (2008). The role of glycogen
synthase kinase 3 in the early stages of Alzheimers’ disease.
FEBS Lett. 582, 3848-3854.
Hernandez, F. et al., (2008). Role of polyglycine repeats in the
regulation of glycogen synthase kinase activity. Protein Pept.
Lett. 15, 586-589.
Mondragon-Rodriguez, S. et al., (2008). Cleavage and
conformationalchanges of tau protein follow phosphorylation
during Alzheimer’s disease. Int. J. Exp. Pathol. 89, 81-90.
Munoz-Fontela, C. et al., (2008). Induction of paclitaxel
resistance by the Kaposi’s sarcoma-associated herpesvirus
latent protein LANA2. J. Virol. 82, 1518-1525.
Navarro, P. et al., (2008). Motor alterations are reduced in mice
lacking the PARK2 gene in the presence of a human FTDP-17
mutant form of four-repeat tau. J. Neurol. Sci. 275, 139-144.
Navarro, P. et al., (2008). Memory and exploratory impairment in
mice that lack the Park-2 gene and that over-express the human
FTDP-17 mutant Tau. Behav. Brain. Res. 189, 350-356.
Perez, M. et al., (2008). Phosphorylated tau in neuritic plaques
of APP(sw)/Tau (vlw) transgenic mice and Alzheimer disease.
Acta Neuropathol. 116, 409-418.
Rubio, A. et al., (2008). Effect of cortistatin on tau phosphorylation
at Ser262 site. J. Neurosci. Res. 86, 2462-2475.
Santa-Maria, I. et al., (2008). Coenzyme q induces tau
aggregation, tau filaments, and Hirano bodies. J. Neuropathol.
Exp. Neurol. 67, 428-434.
Santa-Maria, I. et al., (2008). Binding of tau protein to the
ends of ex vivo paired helical filaments. J. Alzheimers Dis. 13,
177-185.
Utreras, E. et al. (2008). Microtubule-associated protein 1B
interaction with tubulin tyrosine ligase contributes to the control
of microtubule tyrosination. Dev. Neurosci. 30, 200-210.
Villoslada, P. et al. (2008). Immunotherapy for neurological
diseases. Clin. Immunol. 128, 294-305.
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Colaboración en la organización del “V Simposio: Avances en la enfermedad de Alzheimer”, Fundación Reina Sofía.
Research summary
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Doctoral theses
Ismael Santa-Maria. (2008) “Estudio sobre la fosforilación y agregación de la proteína de tau y su posible relación con la enfermedad de
Alzheimer”. U.A.M. Directores: Francisco José Moreno Muñoz y Félix Hernández Pérez.
Alicia Rubio Garrido (2008). “Implicaciones de la proteína tau y la cortistatina en la progresión de la enfermedad de Alzheimer”. U.A.M. Directores: Jesús
Avila de Grado y Mar Pérez Martínez.
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Awards
Premio de la Real Academia de Doctores de España a la mejor tesis en el área de Bioquímica (2008) a Ismael Santa-María.
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Neuronal repair and molecular therapy in neurodegeneration. Spinocerebellar ataxias
Research summary
Many neurogenetic diseases are characterized by a progressive neurodegenerative process in which selective
populations of neurons become dysfunctional and eventually die. Model diseases in this respect are the
spinocerebellar ataxias, which are characterized by neurodegeneration affecting the cerebellum, brainstem
and spinal cord. Our group studies neuronal dysfunction and death processes to find pathways to promote
neuronal survival and repair with the prospects of developing new therapeutic tools.
Research summary
Staff
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We have focused our attention on Friedreich´s ataxia, a hereditary neurological disorder resulting from a
deficiency of frataxin, which is a mitochondrial protein encoded for by the nuclear genome. Our aims are
directed to a deeper understanding of neurodegeneration and the development of experimental molecular
therapy approaches. Thus we are also very interested in the optimization of the technologies for gene transfer
to cells of the central nervous system. In this context, we use lentiviral and herpesviral vectors for neuronal
gene transfer in order to validate possible therapeutic targets, perform functional genomic analyses and design
novel gene therapy approaches.
Thus, we use cell models to study the molecular changes triggered by frataxin gene deficiency within mammalian
neurons. These studies may facilitate the identification of novel therapeutic targets not only for Friedreich´s
ataxia but also for other neurological diseases characterized by a prominent mitochondrial dysfunction.
Likewise, we also explore therapeutic approaches based on possible drugs (or biomolecules) able to either
increase frataxin expression or compensate for frataxin deficiency in mature mammalian neurons
We have also used a Friedreich´s ataxia animal model to assay a gene therapy strategy based on frataxin
gene transfer using herpesviral vectors. This project aims to establish a proof-of-principle about the suitability
of gene therapy for recessive spinocerebellar ataxias.
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Neuronal repair and molecular therapy in neurodegeneration. Spinocerebellar ataxias
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Figure 1. Mouse cerebellar Purkinje neuron in primary culture.
Figure 2. Mitochondrial localization of frataxin in cerebellar granule
neurons after viral vector-mediated gene transfer.
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Molecular Neurobiology
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Neuronal repair and molecular therapy in neurodegeneration. Spinocerebellar ataxias
Group Leader:
Javier Díaz Nido.
Postdoctorals:
Juan Carlos Corona Castillo
Sara Pérez Luz
Alfredo Giménez-Cassina (durante 2007)
Predoctoral Fellows:
Yurika María Katsu Jiménez
Gloria Mª Palomo Carrasco
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Neuronal repair and molecular therapy in neurodegeneration. Spinocerebellar ataxias
Publications
Gimenez-Cassina, A., Lim, F. and Diaz-Nido, J. (2007). Gene transfer into Purkinje cells using herpesviral amplicon vectors in cerebellar
cultures. Neurochem Int. 50, 181-8.
Pastrana, E., Moreno-Flores, M.T., Avila, J., Wandosell, F., Minichiello, L. and Diaz-Nido, J. (2007) BDNF production by olfactory ensheathing
cells contributes to axonal regeneration of cultured adult CNS neurons. Neurochem Int. 50, 491-8.
Gomez-Sebastian, S., Gimenez-Cassina, A., Diaz-Nido, J., Lim, F. and Wade-Martins, R. (2007). Infectious delivery and expression of a
135 kb human FRDA genomic DNA locus complements Friedreich’s ataxia deficiency in human cells. Mol. Ther. 15, 248-54.
Lim, F., Palomo, G.M., Mauritz, C., Giménez-Cassina, A,. Illana, B., Wandosell, F. and Díaz-Nido, J. (2007). Functional recovery in a
Friedreich’s ataxia mouse model by frataxin gene transfer using an HSV-1 amplicon vector. Mol. Ther. 15, 1072-8.
Simón, D., Benitez, M.J., Gimenez-Cassina, A., Garrido, J.J., Bhat, R.V., Díaz-Nido, J. and Wandosell, F. (2008) Pharmacological inhibition of GSK-3 is not
strictly correlated with a decrease in tyrosine phosphorylation of residues 216/279. J Neurosci Res. 86, 668-74.
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El grupo de investigación constituye también la U748 del área de Neurogenética del Centro de Investigación Biomédica en Red de
Enfermedades Raras (CIBERER).
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Molecular basis of neuronal plasticity
Research summary
Research summary
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Publications
Synaptic plasticity (SP) is a basic property of the normal operation of the nervous system (NS) that allows
synaptic contacts to regulate its efficiency depending on the recent history of sustained activity. SP is a
key element during development and regeneration, and is also required for memory function and learning.
SP shows up in diverse forms, some potentiate and others depress synaptic efficiency, some exercise
more durable effects and other more transitory ones. However, all of them share a common messenger:
calcium. Intracellular calcium oscillations initiate the signalling cascades responsible for SP phenomena.
These are mostly mediated by calmodulin (CaM), a small protein, very abundant in the NS, that acts
discriminating signals and modulating the activity of their multiple effectors. Our research group is interested
in CaM’s role in the synaptic environment and, in particular, in the study of CaM sequestering proteins,
such as Neurogranin (Ng) and GAP-43, and their involvement in intracellular signalling pathways of special
relevance to the SP mechanisms. Our working hypothesis foresees that cognitive deficits observed in Ng or
GAP-43-deficient animals are due to alterations of CaM availability to their different effectors. Our group
develops and uses cellular models of SP to analyze the expression, subcelular localization, modifications and
interactions of Ng and GAP-43. Our interest in the dynamics of the processes involved drives us to carry out “in
vivo” studies and to use advance microscopy techniques. In summary, we work to disclose why Ng and GAP-
43 are necessary to maintain the normal levels of cognitive performance and hope to contribute to develop
strategies aimed at its reestablishment in pathologic cases.
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Molecular basis of neuronal plasticity
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Figure 1. Ca2+/CaM signalling in the post-synaptic element.
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Figure 2. Typical clustering of Neurogranin in the somatodendritic compartment (CA1, Hippocampus).
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Molecular basis of neuronal plasticity
Group Leader:
F. Javier Díez Guerra
Predoctoral Fellows:
Irene Domínguez González
Technical Assistance:
Alberto Garrido García
Research summary
Students:
Beatriz Andrés Pans
Lara Durán Trío
Jon Díaz Fauce
Diego Sanz Fuentes
Staff
Publications
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Molecular basis of neuronal plasticity
Publications
Domínguez-González, I., Vázquez-Cuesta, S.N., Algaba, A. and Díez-Guerra, F.J. (2007). Neurogranin binds to phosphatidic acid
and associates to cellular membranes. Biochemical Journal 404 (1), 31-43.
Fernández-Sánchez, E., Díez-Guerra, F.J., Cubelos, B., Giménez, C. and Zafra, F. (2008). Mechanisms of endoplasmic reticulum export of
the glycine transporter GLYT1. Biochemical Journal 409 (3), 669-81.
Research summary
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Molecular Neurobiology
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Molecular and cellular mechanisms for synaptic plasticity
Research summary
Research summary
Staff
Doctoral theses
My research group is particularly interested in the molecular bases for learning and memory. Specifically, we
investigate how synaptic connections in the brain are modified in response to experience. This process, known
as synaptic plasticity, is critical for the establishment of functional neuronal circuits during development, and
also for learning and memory in adulthood. During the last few years, we have discovered that neurons fine-tune
their synapses by inserting or removing neurotransmitter receptors at the synaptic membrane. This work led
us to identify multiple components of the intracellular membrane trafficking machinery that control the transport
of receptors at synapses. Thus, we have determined that a complex network of endosomal compartments,
driven by specific GTPases of the Rab family, control the exocytosis and endocitosis of receptors at the
synaptic membrane (Gerges et al. J Biol Chem 279:43870-43878, 2004; Brown et al. Neuron 45:81-94, 2005;
Brown et al. J Neurosci 27:13311-13315, 2007). This process is assisted by molecular chaperones (Gerges
et al. J Neurosci 24:4758-4766, 2004) and motor proteins of the myosin family (Correia et al. Nat Neurosci 11,
457-466, 2008). Finally, the insertion of receptors at the synaptic membrane is driven by a macromolecular
complex known as the exocyst (Gerges et al. EMBOJ 25:1623-1634, 2006). We have recently summarized
this work in a review paper (Greger and Esteban. Curr Opin Neurobiol 17:289-297, 2007).
Upon our recent incorporation to the Centro de Biología Molecular, we have started to investigate the signaling
cascades that couple neuronal activity with the regulation of neurotransmitter receptor trafficking. These
studies involve a combination of electrophysiological techniques, together with fluorescence microscopy and
molecular biology, with the general goal of understanding how individual molecules contribute to neuronal
function in the brain.
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Figure 1. A major experimental approach in the laboratory is the
expression of recombinant receptors and regulatory proteins tagged
with GFP in hippocampal slices, using electrophysiology and
neuronal imaging as functional assays. The laboratory has a strong
multidisciplinary scope, which we believe is essential for the general
goal of understanding how individual molecules contribute to neuronal
function.
Figure 2. Subcellular distribution of motor protein Myosin Va in
neurons and partial colocalization with neurotransmitter receptors.
Co-immunofluorescence labeling of AMPA receptor subunit GluR1
(left panel) with motor protein Myosin Va (middle panel) in primary
hippocampal neurons. Overlay in right panel. Higher magnification of
dendritic branches in lower panels.
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Molecular Neurobiology
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D5
Molecular and cellular mechanisms for synaptic plasticity
Group Leader:
José Antonio Esteban García
Postdoctoral:
Dina Shira Knafo
Predoctoral fellows:
María Royo Cantabrana
Students:
Argentina Lario Lago
Sergio Camero Gigante
Research summary
Staff
Doctoral theses
CBM 2007-2008

Molecular Neurobiology
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D5
Molecular and cellular mechanisms for synaptic plasticity
Doctoral theses
Tyler Brown (2007). Endosomal trafficking of AMPA receptors at hippocampal Synapses. University of Michigan Medical School.
Director:José Antonio Esteban García.
Kristin Arendt (2008). Role of PI(3,4,5)P3 in hippocampal synaptic plasticity. University of Michigan Medical School. Director:José
Antonio Esteban García.
Research summary
Staff
Doctoral theses
CBM 2007-2008

Molecular Neurobiology
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D6
Molecular bases of the glutamatergic synapses: study of glutamate and glycine transporters
Research summary
Extracellular levels of glutamate, the primary excitatory neurotransmitter in the cerebral cortex, are finely
regulated by the activity of high-affinity transport mechanisms, especially GLT1/EAAT2. Increasing experimental
evidences implicate brain glutamatergic abnormalities in the pathophysiology of schizophrenia, particularly at
the NMDA glutamate receptor site. Glycine participates in glutamatergic neurotransmission as a necessary
coagonist at the NMDA receptors. High-affinity glycine transporters in the CNS maintain the glycine at nonsaturating
concentration in the surrounding of the NMDA receptors in the synaptic cleft. This is carried out by
the high affinity glycine transporters present in the central nervous system.
Research summary
Staff
Publications
The activity of GLT1 is regulated by PKC. The activation of PKC promotes the clathrin-dependent internalization
of the transporter, followed by its lysosomal degradation. Our group has demonstrated that the internalization
process is dependent of the ubiquitylation of GLT1 on lysine residues located in the carboxy terminal tail of
the protein. Exposure to phorbol esters increases the ubiquitylation of GLT1, and this ubiquitylated protein
accumulates in the intracellular compartment. Internalization of ubiquitylated GLT1 was blocked with a
dominant negative dynamine 2 mutant, indicating that the addition of ubiquitin moieties to the transporter in the
membrane precedes its endocytosis. Moreover, we have also identified the specific lysine residues involved
in the process.
Our group has also identified the GLYT1 glycine transporter in neuronal elements through the brain,
closely associated with glutamatergic pathways. There, it is present in the postsynaptic densities of
asymmetric synapses, and it is associated to NMDA receptors through the scaffolding protein PSD95. Our
immunohistochemical studies reveal that in these structures it is also present the glutamate transporter GLT1.
Both GLT1 and GLYT1 seem to operate in concert to regulate the levels of the two NMDA receptor ligands,
glutamate and glycine. Currently we are analyzing the trafficking mechanisms that allow a specific localization
CBM 2007-2008

Molecular Neurobiology
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D6
Molecular bases of the glutamatergic synapses: study of glutamate and glycine transporters
Research summary
Staff
Publications
Figure 1. Subcellular localization of the glutamate transporter GLT1 isoforms in neurons.
CBM 2007-2008

Molecular Neurobiology
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D6
Molecular bases of the glutamatergic synapses: study of glutamate and glycine transporters
Group leader:
Cecilio Giménez Martín
Scientific Staff:
Francisco Zafra (jefe de línea asociado / associated group leader)
Postdoctorals:
Inmaculada González
Predoctorals Fellows:
Enrique Fernández Sánchez
Noemí García
Jaime Martínez de Villarreal
Research summary
Staff
Publications
Technical assistance:
Enrique Núñez
Students:
Raquel Gordo
Aroa Llorente
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Molecular Neurobiology
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D6
Molecular bases of the glutamatergic synapses: study of glutamate and glycine transporters
Publications
Maalem, S., Mutin, M., González-González, I.M., Zafra, F. and Tappaz, M.L. (2008). Selective tonicity-induced expresión of the neuronal
amino-acid transporter SNAT2 in oligodendrocytes in rat brain following systemic hypertonicity. Neuroscience 153, 95-107.
González-González, I. M., García-Tardón, N., Cubelos, B., Giménez, C. and Zafra, F. (2008). The glutamate transporter GLT1b interacts
with the scaffold protein PSD-95. Journal of Neurochemistry 105, 1834-1848.
González-González, I. M., García-Tardón, N., Giménez, C. and Zafra, F. (2008). PKC-dependent endocytosis of the GLT1 glutamate
transporter depends on ubiquitilation of lysines located in a C-terminal cluster. GLIA 56, 963-974.
Zafra, F., Giménez, C. (2008). Glycine transporters and synaptic function. IUBMB Life. 60, 810-817.
Giménez, C., Zafra, F., López-Corcuera, B. and Aragón, C. (2008). Bases moleculares de la hiperplexia hereditaria. Rev. Neurol. 47,
648-652.
Fernández - Sánchez, E., Díez - Guerra, J., Cubelos, B., Giménez, C. and Zafra, F. (2008). Mechanisms of endoplasmic reticulum export
of the glicine transporter GLYT1. Biochemical Journal 409, 669-681.
Research summary
Staff
Publications
CBM 2007-2008

Molecular Neurobiology
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D7
Huntington’s disease and other CNS disorders
Research summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG triplet
repeat expansion coding for a poly-glutamine (polyQ) sequence in the N-terminal region of the huntingtin (htt)
protein. However, the precise mechanism by which mutant-huntingtin elicits its toxicity remains unknown.
We were pioneers in applying conditional transgenesis in mice to study neurodegeneration. This technology
allows exploring what aspects of neuropathology are susceptible to revert upon shut down of the pathogenic
transgene. The conditional mouse model of HD revealed that disease may be reversible (Cell 101: 57-66,
2000) even in advanced stages after neuronal loss has taken place (J. Neurosci. 25, 9773-9781; 2005).
Research summary
Staff
Publications
Regarding the molecular mechanisms by which mutant huntingtin induces pathology, we have explored the
ubiquitin proteasome system (UPS) hypothesis in brain samples (J. Neurosci. 23, 11653-61, 2003), in vitro
with purified aggregates (J. Neurosci. 24, 9361-71, 2004; J. Neurochem. 98, 1585-1596; 2006) and in vivo
by using UPS impairment reporter mice (Trends Neurosci. 27, 66-69, 2004). Concerning the mechanisms
of synaptic dysfunction in HD, we have detected changes in the physiology of the P2X7 ATP-gated calcium
channel (J. Cell Sci. 121: 3717-28, 2008 and FASEB J. in press). Finally, we have also explored the potential
role of the GSK-3 kinase as therapeutic target in HD and its role in the physiology of striatal neurons (EMBO
J. 26: 2743-2754, 2007).
Other activities
Patents
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Molecular Neurobiology
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D7
Huntington’s disease and other CNS disorders
Research summary
Staff
Publications
Other activities
Patents
Figure 1. Inducible mouse model of Huntington’s disease (Tet/HD94)
and a non-transgenic littermate (Control).
Figure 2. Calcium imaging (left) and calcein/propidium iodine survival
assay (right) in primary culture neurons transfected with exonIhuntingtin-Q72-GFP
(Q72) and in wild type (Control) and Tet/HD94
neurons after P2X7 agonist stimulation.
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Molecular Neurobiology
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D7
Huntington’s disease and other CNS disorders
Group Leader:
José Lucas
Postdoctoral:
Celia Cerrato Rivera
Mª del Rosario Fernández Fernández
Owen Howard
Cristina Tomás Zapico
Predoctoral fellows:
Raquel Gómez Sintes
Zaira Ortega Llorente
Research summary
Staff
Publications
Other activities
Technical Assistance:
Desire Ruiz García
Alicia Tomico García
Students:
Marta Fernández Nogales
Enrique Gabande Rodríguez
Visiting scientist:
Miguel Díaz Hernández
Patents
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Molecular Neurobiology
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D7
Huntington’s disease and other CNS disorders
Research summary
Staff
Publications
Other activities
Patents
Publications
Gómez-Sintes, R., Hernández, F., Bortolozzi, A., Artigas, F., Avila,
J., Zaratin, P., Gotteland, J.-P. and Lucas, J.J. (2007). Neuronal
apoptosis and reversible motor deficit in dominat-negative GSK-3
conditional transgenic mice. EMBO J. 26: 2743-2754.
Engel, T., Lucas, J.J., Hernández, F., and Avila, J. (2007).
A mouse model to study tau pathology related with tau
phosphorylation and assembly. J. Neurol. Sci. 257: 250-254.
Hooper, C., Markevich, V., Killick, R., Schofield, E., Anderton, B.,
Rosenblum, K., Bliss, T., Engel, T., Hernandez; F., Avila, J., Lucas,
J.J., Stephenson, J. and Lovestone, S. (2007). Glycogen synthase
kinase-3 inhibition is integral to Long Term Potentiation. Eur. J.
Neurosci. 25(1):81-86.
Valera, A.G., Díaz-Hernández, M., Hernández, F. and Lucas,
J.J. (2007). Testing the possible inhibition of proteasome by
direct interaction with ubiquitylated and aggregated huntingtin.
Brain Res. Bull. 72: 121-123.
García-Martínez, J.M., Pérez-Navarro, E., Xifró, X., Canals,
J.M., Díaz-Hernández, M., Trioulier, Y., Brouillet, E., Lucas, J.J.
and Alberch, J. (2007). BH3-only Proteins Bid and BimEL are
Differentially Involved in Neuronal Dysfunction in Mouse Models
of Huntington’s Disease. J. Neurosci. Res. 85: 2756-69.
Goñi-Oliver, P., Lucas, J.J., Avila, J. and Hernández, F. (2007).
N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3
regulation. J. Biol. Chem. 282: 22406-13.
Ortega, Z., Diaz-Hernandez, M. and Lucas, J.J. (2007). Is the
ubiquitin-proteasome system impaired in Huntington’s disease?
Cell. Mol. Life Sci. 64: 2245-57.
Engel, T., Goñi-Oliver, P., Gómez de Barreda, E., Lucas, J.J.,
Hernández, F. and Avila, J. (2008). Lithium, a potential protective
drug in Alzheimer’s disease. Neurodegener Dis. 5: 247-9.
Engel, T., Goñi-Oliver, P., Gómez-Ramos, P., Morán, M.A.,
Lucas, J.J., Avila, J. and Hernandez, F. (2008). Hippocampal
neuronal subpopulations are differentially affected in double
transgenic mice overexpressing FTDP-17 tau and GSK-3beta.
Neuroscience 157: 772-80.
Diaz-Hernandez, M., Diaz-Hernandez, J.I., Diez-Zaera, M., del
Puerto A., Lucas, J.J., Garrido, J.J. and Miras-Portugal, M.T.
(2008). Inhibition of the ATP-gated P2X7 receptor promotes
axonal growth and branching in cultured hippocampal neurons.
J. Cell Sci. 121: 3717-28.
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Molecular Neurobiology
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D7
Huntington’s disease and other CNS disorders
Other activities
Grupo integrante del Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED).
http://www.ciberned.es/grupojoselucas.aspx.
Research summary
Staff
Publications
Other activities
Patents
CBM 2007-2008

Molecular Neurobiology
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D7
Huntington’s disease and other CNS disorders
Patents
M. T. Miras-Portugal, M. Díaz-Hernandez and J. J. Lucas (2007). Método de diagnóstico/pronóstico in vitro de la corea de
Huntington. UCM/CSIC. P200701351, PCT/ES2008/070092.
R. Gomez-Sintes and J. J. Lucas (2008). Composición y tratamiento combinado de inhibidores de GSK-3 e inhibidores de la vía NFAT/
Fas. CSIC/CiberNed. P200803049.
Research summary
Staff
Publications
Other activities
Patents
CBM 2007-2008

Molecular Neurobiology
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D8
Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration
Research summary
The incidence of neurodegenerative diseases is steadily increasing, particularly in well developed countries,
due to the increase in life-expectancy. For some of them, like Parkinson, Huntington or Alzheimer diseases,
pharmaceutical drugs are useful at early stages of the disease, when neuronal atrophy/loss is moderate.
However, none of them really cure the disease, since they do not halt the neuronal atrophy and death
process.
In this context, research on the basic biology of human neural stem cells (either endogenous or implanted)
acquires special relevance. The prospect is that healthy stem cell derivatives, after implantation, would either
delay disease progression (helping the sick neurons) or actually cure the disease (neuron replacement).
Research summary
Staff
Publications
Doctoral theses
Our research group is interested in understanding basic developmental events during maturation of human
stem cell derivatives, using: 1) Neural stem cells, obtained from fetal or adult human tissue, and already
instructed as neural cells; 2) Embryonic stem cells derived from the inner cell mass of the blastocist, (hES
cells) from which neural stem cells can be easily derived; and 3) Induced pluripotent stem cells (iPSCs),
reprogrammed from somatic adult cells.
Our main research focus is thus on basic developmental events involved in the generation of glia, but particularly
of Dopaminergic, Gaba-ergic and Cholinergic neurons, to learn how to harness the potential that stem cells
may have for therapy of these devastating diseases (like Parkinson, Huntington, Alzheimer/dementia).
Another aspect in which we are interested on is the modification of the intrinsic properties of the neural stem
cells through genetic modification, to turn them into “biological mini-pumps” (for instance for the secretion of
neurotrophic factors) , or to instruct them or guide their differentiation towards specific, on-demand desired
phenotypes after implantation. Last, we are developing nanotools to label and track the cells in vivo, study their
cell biology and to develop early diagnostic tools for Alzheimer disease.
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Molecular Neurobiology
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D8
Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration
Research summary
Staff
Publications
Doctoral theses
Figure 1. Human neural stem cells derived from the ventral
mesencephalon differentiated for the generation of dopaminergic
neurons. Stain: Tyrosine Hydroxylase (TH, Cy5, green), MAP2 (Cy3,
red) and nuclei (Hoescht, blue). Obj 63.
Figure 2. Human embryonic stem cells (hES) under proliferation conditions,
and after differentiation towards dopaminergic neuronas. The cells were
staind for pluripotency markers like Oct4 and SSEA4, neuronal marker
(β-III-tubulin) and dopaminergic markers (TH and Nurr1).
CBM 2007-2008

Molecular Neurobiology
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D8
Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration
Group leader:
Alberto Martínez Serrano
Scientific Staff:
Milagros Ramos Gómez
Mª Isabel Liste Noya
Postdoctorals:
Claudia G. Castillo Martín
del Campo
Carlos Bueno López
Elise T. C. Courtois
Research summary
Staff
Publications
Doctoral theses
Predoctoral Fellows:
Elisa García García
Emma Mª González Seiz
Technical Assistance:
Juliana Sánchez García
Beatriz Moreno Moreno
Marta Gonzalez Mella
Ignacio Tardieu de Chorro
Isabel Manso (dedicación compartida con línea J. Satrústegui)
Barbara B. Sesé Cobos (adscrita a línea J. Satrústegui)
Students:
Laura López Medina
Kattarina Gapp
Miguel Barrado de Álvaro
CBM 2007-2008

Molecular Neurobiology
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D8
Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration
Publications
Cacci, E., Villa, A., Parmar, M., Mandhal, N., Lindvall, O., Martínez-Serrano, A. and Kokaia, Z. (2007). Generation of human
cortical neurons from a new immortal fetal neural stem cell line. Exp. Cell Res., 313, 588-604.
Liste, I., García-García, E., Bueno, C. and Martínez-Serrano, A. (2007). Bcl-XL modulates the differentiation of human neural stem cells.
Cell Death Diff., 14, 1880-1892.
Anwar, M.R., Andreasen, C.M., Lippert, S.K., Zimmer, J., Martinez-Serrano, A. and Meyer, M. (2008). Dopaminergic differentiation of
human neural stem cells mediated by cocultured rat striatal brain slices. J. Neurochem., 105, 460-470
Ekici, M., Hohl, M., Schuit, F., Martínez-Serrano, A. and Thiel, G. (2008). Transcription of genes encoding synaptic vesicle proteins in
human neural stem cells: chromatin accessibility, histone methylation pattern, and the essential role of rest. J. Biol. Chem, 283,
9257-9268.
Shah, K., Hingtgen, S., Kasmieh, R., Figueredo, J.L., García-García, E., Martinez-Serrano, A., Breakefield, X. and Weissleder, R.
(2008). Bimodal viral vectors and in vivo imaging reveal the fate of human neural stem cells in experimental glioma model. J. Neurosci.,
28, 4406-4413.
Research summary
Staff
Publications
Doctoral theses
CBM 2007-2008

Molecular Neurobiology
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D8
Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration
Doctoral theses
Carlos Bueno Lopez. Terapia génica ex vivo al Sistema Nervioso Central mediante células troncales de origen humano utilizando
vectores de recombinación homóloga. 23 de marzo de 2007. U.A.M. Director: Alberto Martínez Serrano.
Elise Therese Carmen Courtois. Estudios de las propiedades de células troncales neurales humanas derivadas de mesencéfalo
ventral y su modificación por Bcl-XL: Implicación para terapia celular en la enfermedad de Parkinson. 20 de Junio 2008. U.A.M. Director:
Alberto Martínez Serrano.
Research summary
Staff
Publications
Doctoral theses
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Molecular Neurobiology
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D9
Calcium signalling in mitochondria and insulin/leptin signalling during ageing
Research summary
Research summary
Staff
Publications
Ca 2+ entry in mitochondria is important in cell Ca 2+ signaling, but its persistence in mitochondria is associated
with mitochondrial dysfunction and cell death. We are interested in the study of systems for Ca 2+ signaling in
mitochondria that do not require Ca 2+ entry in the organelle, the aspartate-glutamate carriers (AGC) aralar and
citrin, and the ATP-Mg/Pi carriers, or Short CaMCs (SCaMCs). Both AGCs and SCaMCs have calcium binding
domains facing the intermembrane space and which are activated by Ca 2+ without the need of calcium entry
in mitochondria. Aralar and citrin, the brain and liver AGCs, are components of the malate-aspartate NADH
shuttle. Using mice with selective disruption of aralar or citrin, we have shown that both AGC isoforms are
regulated by Ca 2+ at concentrations lower than those required to activate the Ca 2+ uniporter and are required
to transmit very small Ca signals to brain or beta-cell mitochondria. We are now interested in studying the role
of these small Ca 2+ signals in brain metabolism and the role of aralar and SCaMCs in human pathology.
Insulin resistance is associated with aging in rodents and humans. We have found hyperleptinemia and central
leptin resistance in aged rats, and we have observed that they also show central insulin resistance. These
alterations in the central action of leptin and insulin could play a key role in the development of overall insulin
resistance along ageing. We are currently studying the possible involvement of leptin and other adipokines in
age-associated changes in insulin sensitivity and the alteration of insulin response in muscle together with the
reversibility of these changes by means of caloric restriction.
Other activities
Doctoral theses
CBM 2007-2008

Molecular Neurobiology
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D9
Calcium signalling in mitochondria and insulin/leptin signalling during ageing
Group Leader:
Jorgina Satrústegui Gil-Delgado
Scientific Staff:
Elena Bogónez Peláez
Jose M. Carrascosa Baeza
Postdoctorals:
Beatriz Pardo Merino
Laura Contreras Balsa
Santiago Cavero Martinez
Technical Assistance:
Bárbara Sesé Cobos
Isabel Manso Gavilán
Visitor Scientist:
Araceli del Arco Martínez
(Universidad de Castilla-la-Mancha)
Research summary
Staff
Publications
Other activities
Doctoral theses
Predoctoral Fellows:
Patricia Mármol Carrasco
Javier Traba Domínguez
Ignacio Amigo de la Huerga
Irene Llorente Folch
Alain Juan de Solis
Students:
Almudena Urbieta Magro
Paula Pérez Pardo
Carlos Rueda Diez
Alicia Ortiz Temprado
Ana Quintas Gorozarri
Berta Pérez Alarcón
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Molecular Neurobiology
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D9
Calcium signalling in mitochondria and insulin/leptin signalling during ageing
Research summary
Staff
Publications
Other activities
Doctoral theses
Publications
Satrústegui, J., Pardo, B. and del Arco, A. (2007). Mitochondrial
transporters as novel targets for intracellular Ca2+ Signalling.
Physiological Reviews 87: 29-67.
Contreras, L., Gómez-Puertas, P., IIjima, M., Kobayashi, K., Saheki,
T., and Satrústegui, J. (2007). Ca2+ activation kinetics of the two
aspartate-glutamate mitochondrial carriers aralar and citrin:
role in heart malate-aspartate NADH shuttle. J. Biol. Chem
282:7098-106.
Satrustegui, J., Contreras, L., Ramos, M., Marmol, P., del Arco, A.,
Saheki, T. and Pardo, B. (2007). Role of aralar, the mitochondrial
transporter of aspartate-glutamate, in brain N-acetylaspartate
formation and Ca2+ signalling in neuronal mitochondria.
J.Neurosci. Res. 85: 3359-3366.
Traba, J., Froschauer, E., Wiesenberger,G., Satrústegui, J.
and del Arco, A. (2008). Yeast mitochondria import ATP through
the calcium-dependent ATP-Mg/Pi carrier Sal1p, and are ATP
consumers during aerobic growth in glucose. Mol Microbiol
69: 570-85.
Escrivá, F., Gavete, M.L., Fermín, Y., Pérez, C., Gallardo, N.,
Alvarez, C., Andrés, A., Ros, M. and Carrascosa, J.M. (2007).
Effect of age and moderate food restriction on insulin sensitivity
in Wistar rats: role of adiposity. Journal of Endocrinology 194,
131-141.
García-San Frutos, M., Fernández-Agulló, T., De Solís, A.J.,
Andrés, A., Arribas, C., Carrascosa, J.M. and Ros, M. (2007).
Impaired central insulin response in aged wistar rats: role of
adiposity. Endocrinology 148: 5238- 5247.
Gallardo, N, Bonzón-Kulichenko, E, Fernández-Agulló, T, Moltó,
E, Gómez-Alonso, S, Blanco, P., Carrascosa, JM, Ros, M, Andrés,
A (2007). Tissue-specific effects of central leptin on liver and white
adipose tissue lipid metabolism. Endocrinology 148,
5604 – 5610.
Pérez, C., Fernández-Agulló, T., De Solís, A.J., Ros, M.,
Andrés, A. and Carrascosa, J.M. (2008). Effects of chronic
acarbose treatment on adipocyte insulin responsiveness,
serum levels of leptin and adiponectin and hypothalamic
NPY expression in obese diabetic Wistar rats. Clinical and
Experimental Pharmacology and Physiology 35: 256 – 261.
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Molecular Neurobiology
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D9
Calcium signalling in mitochondria and insulin/leptin signalling during ageing
Other activities
Curso Teórico-Práctico sobre Bioenergética Mitocondrial y Apoptosis. Fecha: 15-19 Septiembre 2008. Desarrollado en CBMSO,
IIB-CSIC, UCM, CNIC. Organizado por Consorcio “MITOLAB-CM” del Programa de Actividades de I+D entre Grupos de Investigación
en Biociencias de la Comunidad de Madrid en colaboración con Centro de Investigación Biomédica en Red de Enfermedades Raras
“CIBERER”.
Research summary
Staff
Publications
Other activities
Doctoral theses
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Molecular Neurobiology
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D9
Calcium signalling in mitochondria and insulin/leptin signalling during ageing
Doctoral theses
Laura Contreras Balsa. Marzo 2007. Caracterización de la activación por calcio de aralar y citrina, los transportadores mitocondriales
de aspartato-glutamato. U.A.M. Director: Jorgina Satrústegui.
Research summary
Staff
Publications
Other activities
Doctoral theses
CBM 2007-2008

Molecular Neurobiology
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D10
Molecular pathology of Alzheimer’s disease
Research summary
Research summary
Staff
Our group is involved in the search of novel therapeutic targets for familial (FAD) and sporadic (SAD) Alzheimer’s
disease, based on the hypothesis that mutations in FAD, or the presence of virus like herpes simplex 1
(HSV‐1) in SAD, could act in concert with the oxidative stress (EO) associated with normal aging to induce
neurodegeneration. Regarding FAD, we have prepared cell models –human neuroblastoma stably expressing
wild type or mutant APP or PSEN1‐ and we have found that mutant cells are more sensitive to EO. Our SAD
model is based upon the interaction between HSV‐1 infection and EO in human neuroblastoma cells. We have
found that HSV1 regulates autophagy ‐inducing the first steps and inhibiting the execution‐; furthermore, HSV‐1
induces in the cells the most characteristic markers of Alzheimer’s disease: i) an increase in phosphorylated
tau, mainly localized in the viral replication centres and ii) an activation of the APP amyloidogenic processing,
which results in the accumulation of Ab in autophagic vesicles. These data, together with the association of
two genes relevant to HSV‐1 infection (TAP2 y EIF2AK3) with AD risk, support the involvement of HSV‐1
on AD pathogenesis. We have also proved that EO specifically modulates cholesterol metabolism in the
neuroblastoma cells, that the silencing of HMGCR, a key enzyme of cholesterol biosynthesis, inhibits the EO
induced apoptosis, and that HMGCR shows genetic association with SAD. In summary, these data reveal a
connection among EO, cholesterol and apoptosis in the pathogenesis of Alzheimer’s disease.
Publications
Other activities
Patents
Doctoral theses
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Molecular Neurobiology
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D10
Molecular pathology of Alzheimer’s disease
Research summary
Staff
Publications
Other activities
Patents
Doctoral theses
Figure 1. HSV 1 induces authophagy and intracellular Ab accumulation. SKNMC human neuroblastoma cells stably overexpressing APP were
infected with HSV 1, and visualized by electron microscopy (upper panels) or by fluorescence microscopy with antibodies specific for LC3 (central
panels) or Ab peptide (lower panels).
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Molecular Neurobiology
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D10
Molecular pathology of Alzheimer’s disease
Group Leader:
Fernando Valdivieso Amate
Scientific Staff:
Maria Jesús Bullido
Postdoctorals:
Jesús Aldudo Soto
María Recuero Vicente
Research summary
Staff
Publications
Other activities
Predoctoral Fellows:
Fernando Guzmán Sánchez
Teresa Muñoz de Galdeano
Diego Muñoz Santos
Soraya Santana Martínez
Esther Serrano Saiz
Raquel Tenorio Vela
María del Carmen Vicente Cenzano
Technical Assistance:
Sandra Herranz Gómez
Ana Martínez García
Susana Molina Arranz
Isabel Sastre Merlín
Patents
Doctoral theses
CBM 2007-2008

Molecular Neurobiology
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D10
Molecular pathology of Alzheimer’s disease
Research summary
Staff
Publications
Bullido, M. J., Martínez-García, A., Artiga, M. J., Aldudo, J., Sastre, I., Gil, P., Coria, F., Muñoz, D. G., Hachinski, V., Frank A. and Valdivieso,
F. (2007) A TAP2 genotype associated with Alzheimer’s disease in APOE4 carriers. Neurobiology of Aging 28, 519-523 .
Burgos, J. S., Ramírez, C., Brachet, A., Alfaro, J. M., Sastre, I. and Valdivieso, F. (2007). Changes in immunoglobulin levels related to
herpes simplex virus type 1 brain infection in pregnant mice. Journal of Neurovirology 13, 233-241.
Burgos, J. S. and Valdivieso, F. (2007). Understanding the relationship between ApoE and HSV-1 and its possible significance in
Alzheimer´s disease. Future Virology 2, 239-242.
Moreira, P. N., Pozueta, J., Pérez-Crespo, M., Valdivieso, F., Gutiérrez-Adán, A. and Montoliu, Ll. (2007). Improving the generation of
genomic-type transgenic mice by ICSI. Transgenic Research 16, 163-168.
Burgos, J. S., Ramírez, C., Brachet, A., Alfaro, J. M., Sastre, I. and Valdivieso, F. (2007). Apoliprotein E genotype influences vertical
transmission of herpes simplex virus type 1 in a gender specific manner. Aging Cell 6, 841-2.
Bullido, M. J., Martínez-García, A., Tenorio, R., Sastre, I., Muñoz, D. G., Frank, A. and Valdivieso, F. (2008). Double stranded RNA
activated EIF2 a kinase (EIF2AK2; PKR) is associated with Alzheimer´s disease. Neurobiology of Aging 29, 1160-1166.
Martínez-García, A., Aldudo, J., Recuero, M., Sastre, I., Vilella-cuadrada, E., Rosich-Estrago, M., Frank, A., Valdivieso, F. and Bullido, M.
J. (2008). Presenilin-1 polymorphism modulates the risk of Alzheimer’s disease conferred by ApoE4. Dementia and Geriatric Cognitive
Disorders 26, 440-444.
Publications
Other activities
Patents
Doctoral theses
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Molecular Neurobiology
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D10
Molecular pathology of Alzheimer’s disease
Other activities
F. Valdivieso. Organización de: “Fisiopatología y farmacología de la enfermedad de Alzheimer”.
Research summary
Staff
Publications
Other activities
Patents
Doctoral theses
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Molecular Neurobiology
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D10
Molecular pathology of Alzheimer’s disease
Patents
F. Valdivieso, M. J. Bullido, A. Martínez García (2007). Método para la identificación de compuestos para el tratamiento de enfermedades
neurodegenerativas. Nº Solicitud: P200702997. País de Prioridad: España. Entidad titular: U.A.M./C.S.I.
Research summary
Staff
Publications
Other activities
Patents
Doctoral theses
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Molecular Neurobiology
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D10
Molecular pathology of Alzheimer’s disease
Doctoral theses
Mª Carmen Vicente Cenzano. 2007. Convergencia de estrés de retículo endoplásmico y estrés oxidativo como modelo celular de neurogeneración.
Universidad Autónoma de Madrid. Directores: María Recuero y Fernando Valdivieso.
Esther Serrano Saiz. 2007. Efecto de la proteína presentadora de antígenos TAP en la infección in vivo del virus herpes simplex tipo
1 y generación de modelos transgénicos para su estudio. Universidad Autónoma de Madrid. Directores: Javier S. Burgos y Fernando
Valdivieso.
Raquel Tenorio Vela. 2007. La homocisteína como factor de riesgo par la enfermedad de Alzheimer. Universidad Autónoma de Madrid.
Directores: María J. Bullido y Fernando Valdivieso.
Ana Martínez García. 2008. Análisis de asociación genética para el estudio de la patogénesis de la enfermedad de Alzheimer. Universidad
Autónoma de Madrid. Directores: María J. Bullido y Fernando Valdivieso.
Research summary
Staff
Publications
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Patents
Doctoral theses
CBM 2007-2008

Molecular Neurobiology
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D11
Molecular mechanism of neurodegeneration and regeneration
Research summary
Our group is devoted to the analysis of molecular mechanism triggered by neurodegenerative processes. We
try to understand key signals that regulate cellular morphogenesis, and how these putative pathways may
be defective in some pathological situations. As a second challenge we would like to propose regeneration
alternatives.
Analyzing some cellular models of neurodegeneration, we have defined that the increases the activity of
glycogen synthase kinase 3 (GSK-3), correlate with neuronal degeneration, and in some cases with neuronal
death. The pharmacological inhibition or the over-expression of a dominant-negative mutant of GSK-3 in
neuron cells efficiently prevents prion-induced cell death. Second, we have defined that an increase of GSK3
activity does not necessarily correlate with neurodegeneration
Research summary
Staff
Publications
Other activities
In some neurodegeneration mouse models we have defined that the pathway PI3K-Akt-GSK3 is deregulated
being responsible, at least in part, of the final neurodegeneration process. On the other hand, we determined
that some hormones, such as estradiol modulated neuroprotection through the inhibition of GSK3. Our work
is trying to identify elements implicated in this neuroprotective effect (Supervisor F. Wandosell).
We try to understand key signals that regulate neuronal morphogenesis (acquisition of neuronal polarity).
Using a model of cultured hippocampal neurons, we have defined that GSK3 and the NF-kB inhbitor (IkBa)
are essential to form an axon and later they play an important role to maintain the axonal properties, such
as the axon initial segment function. Thus, we are trying to define more deeply the mechanisms involved in
axon and axon initial segment formation and maintenance, which are critical for the final function of neurons
(Supervisor J.J. Garrido).
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Molecular Neurobiology
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D11
Molecular mechanism of neurodegeneration and regeneration
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CBM 2007-2008

Molecular Neurobiology
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D11
Molecular mechanism of neurodegeneration and regeneration
Group Leader:
Francisco Wandosell Jurado
Scientific Staff:
Juan José Garrido Jurado
Mª José Benítez Moreno
María José Pérez Alvarez
Research summary
Staff
Publications
Other activities
Predoctoral Fellows:
Olga Varea Abbad
Héctor Diez Nuño
Mónica Tapia Pacheco
Ana del Puerto del Pino
Irene Martínez Carrasco
Diana Sánchez Ponce
Students:
Maria Isabel Escoll
Jonay Poveda
Technical Assistance:
Lara Rodestein
Lara Ordóñez Gutiérrez
Nuria Peralta Cañadas
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Molecular Neurobiology
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D11
Molecular mechanism of neurodegeneration and regeneration
Research summary
Staff
Publications
Other activities
Publications
Pastrana, E., Moreno-Flores, M.T., Avila, J., Wandosell, F. ,
Minichiello, L. and Diaz-Nido, J. (2007). BDNF production by
olfactory ensheathing cells contributes to axonal regeneration
of cultured adult CNS neurons. Neurochemistry Int. 50,
491-498.
Salcedo, M., Cuevas, C., Alonso, J.L., Otero, G., Faircloth, G.,
Fernandez-Sousa, J.M., Avila, J. and Wandosell, F. (2007).
The marine sphingolipid-derivated compound ES 285 triggers
an atypical cell death pathway. Apoptosis 12, 395-409.
Simon, D., Varea, O., Garrido, J.J. and Wandosell, F. (2006).
Role of GSK3/Shaggy in neuronal cell biology. In “Glycogen
Synthase Kinase 3(GSK-3) and Its Inhibitors”. Wiley-Intescience,
John Wiley and Sons, Inc. Ed. A. Martinez, A. Castro and M
Medina. Chapter 3, pgs : 45-82
Lim. F., Palomo, G. M., Mauritz, C., Giménez-Cassina, A..,
Illana, B., Wandosell, F. and Díaz-Nido, J. (2007). Functional
recovery in a Friedreich´s ataxia mouse model by frataxin gene
transfer using a HSV-1 amplicon vector. Molecular Therapy 15,
1072-1078.
Garrido, J.J., Simon, D., Varea, O. and Wandosell, F. (2007).
GSK3alpha and GSk3beta are necessary for axon formation.
FEBS Lett. 581, 1579-1586.
Anton, I. M., Jones, G. E., Wandosell, F., Geha, R. and Ramesh,
N. (2007). WASP-interacting protein (WIP): working
in polymerisation and much more. Trends in Cell Biol 17,
555-562.
Simón, D., Benitez, M.J., Gimenez-Cassina, A., Garrido, J.J., Bhat,
R.V., Díaz-Nido, J. and Wandosell, F. (2008). The pharmacological
inhibition of GSK-3 is not strictly correlated with a decrease
in tyrosine phosphorylation of residues 216/279. J. Neurosci.
Res. 86, 668-674.
Sanchez-Ponce, D., Tapia, M., Muñoz, A. and Garrido, J.J. (2008).
New role of IKK alpha/beta phosphorylated IkappaB alpha in
axon outgrowth and axon initial segment development. Mol. Cell.
Neurosci., 37, 832-844.
Diaz-Hernandez, M., Del Puerto, A., Diaz-Hernandez, J. I., Diez-
Zaera, M., Lucas, J. J., Garrido, J. J. and Miras-Portugal, M. T.
(2008) Inhibition of the ATP-gated P2X7 receptor promotes axonal
growth and branching in cultured hippocampal neurons. J Cell Sci.
22, 3717-3728.
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Molecular Neurobiology
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D11
Molecular mechanism of neurodegeneration and regeneration
Other activities
Acuerdo de Colaboración con FAES FARMA.
Acuerdo de Colaboración con NOSCIRA.
Acuerdo de Colaboración con PHARMAMAR hasta 2005.
Este grupo también forma parte del Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed):
http://www.ciberned.es/grupofranciscowandosell.aspx.
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Molecular Neurobiology
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D12
Role of lipids in neuronal physiology and pathology
Research summary
Our final goal is to understand the role of lipids in neuronal physiology and pathology. To this aim we will
analyze transgenic mice in which the metabolisms of cholesterol or sphingomyelin are altered. These mice
mimic the mental retardation syndromes desmosterolosis and Niemann Pick disease type A (NPA). Our
research lines focus on the analysis of neuronal lipid and protein polarized transport and synapse functionality.
Recently, we have demonstrated that NPA affected neurons show accumulation of sphingomyelin at their
plama membrane. This leads to the impaired endocytosis of molecules and to their lack of axonal polarization.
We have also shown that sphingomyelin accumulation affects the membrane of the synapse. This results in
altered presynaptic plasticity. We believe our research will contribute to create knowledge on lipid physiology
in the brain and on the causes and possible treatments of mental retardation associated to lipidosis.
Research summary
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Molecular Neurobiology
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D12
Role of lipids in neuronal physiology and pathology
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Publications
Figure 1. Double immunofluorescence of an hippocapal primary
neuron in culture stained with antibodies against the cytoskeletal
proteins MAP2 (red) and Tau (green). The image is representative of
the extreme molecular polarization.
Figure 2. Electronic microscope image of a synapse of the mouse
hippocampus. The image shows in detail the pre and postsynaptic
regions, the active zone and the vesicles.
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Molecular Neurobiology
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D12
Role of lipids in neuronal physiology and pathology
Scientific Staff:
María Dolores Ledesma Muñoz
Postdoctoral :
Paola G. Camoletto
GRUPO EMERGENTE
(incorporación al CBMSO en abril 2008)
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Molecular Neurobiology
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D12
Role of lipids in neuronal physiology and pathology
Publications
Bulloj, A., Leal, M.C., Surace, E.L., Zhang, X., Xu, H., Ledesma, M.D., Castano, E.M. and Morelli, L. (2008). Detergent resistant
membrane-associated IDE in cultured cells and brain tissue: Relevance to Abeta and insulin degradation. Mol Neurodegener. 3 (3), 22.
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Molecular Neurobiology
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D13
Molecular pathways to Neurodegeneration. Cellular and Animal Models: Role of post-translational
modification of Tau in its degradation by calpains.
Felix Hernández. Research summary
Línea de investigación
Calpain is one of the main proteases activated by calcium and has been implicated in Alzheimer disease.
Thus, elevated cleavage and activation of calpain has been previously reported in early-stage AD suggesting
that abnormalities in calcium homeostasis might be involved in the pathophysiology of the disease. In relation
with tau protein, it has been demonstrated that hyperphosphorylated tau is resistance to calpain-dependent
proteolysis. To study the interaction between tau, phosphorylation and calpain, we will be use transgenic mice
which overexpres the enzyme GSK-3β and tau protein. We will also cross both transgenic lines and the resulting
double transgenic mice will allow us to test the synergistic contribution of both proteins in Alzheimer’s
disease and to study their relationship with the calpain system. In addition, we have recently described that
calpain activation produces a truncation of GSK-3 which remove the inhibitory domain. We are going to study
that cleavage in our transgenic models to validate GSK-3 inhibitors as pharmacological tools in Alzheimer
disease.
CBM 2007-2008

Molecular Neurobiology
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D13
Molecular pathways to Neurodegeneration. Cellular and Animal Models: Role of post-translational
modification of Tau in its degradation by calpains.
Línea de investigación
Figure 1. Diagram showing how altered calcium homeostasis following NMDA receptor activation may contribute to the physiology and eventually
to neuropathological activation of the calpain/GSK3/CDK5 pathway.
CBM 2007-2008