Thursday, 5th December 2019

Molecular bases of inherited metabolic diseases and research in molecular therapies

 2017 02 07 Grupo Lourdes RuizDesviat 02 400px


Lourdes Ruiz Desviat 




Research summary:

The group belongs to the Biomedical Network Research Centre for Rare Diseases (CIBERER) and to Hospital La Paz Institute for Health Research (IdiPaz) and collaborates actively with Centro de Diagnóstico de Enfermedades Moleculares (CEDEM, Facultad de Ciencias, UAM, Our work is focused on the research on the molecular basis of different inherited metabolic diseases (IMD), of their cellular pathophysiology and of the molecular mechanism of mutations identified in patients with the aim of identifying therapeutic targets and developing new genetic and pharmacological treatment strategies. New genomic technologies based on arrays and whole exome sequencing have been implemented for gene identification and mutation detection in IMD. Gene capture and exome enrichment strategies for genes responsible for specific diseases are being validated for genetic diagnosis. We have recently published the identification of novel regulatory defects in the multienzymatic mitochondrial complex BCKDH involved in disease.


Figure 1: Antisense oligonucleotide treatment in Pahenu2/+ mice. (A) Mice were treated with i.v. injections with VMO-ex11 at the indicated doses and sacrificed at day 4 after the first injection. (B) Blood L-Phe levels, (C) RT-PCR analysis of Pah-mRNA from liver, and (D) Western blot analysis showing PAH protein levels in liver. (E) PAH enzyme activity relative to control wild-type levels. (Gallego-Villar et al. 2014)


Figure 2: Generation and characterization of MMA cblB type patient-specific iPSC lines. A). Patient iPSC stained for alkaline phosphatase activity. B). Normal karyotype of patient iPS cell line. C-F). Representative colonies of patient iPSC stained positive for the pluripotency-associated markers. G-I). Immunofluorescence analysis of iPSC differentiated in vitro showing the potential to generate cell derivatives of all three primary germ cell layers. J). Metahylatin analysis of the OCT4 promoter by bisulphite sequencing. K). Direct sequenced of genomic DNA from patient iPSC identifying the mutations.


In our research we use conventional protein expression systems, both prokaryotic and eukaryotic, as well as patients' cells and murine models of disease. We have generated iPS cells derived from patients' fibroblasts to further differentiate them into hepatocytes, neural precursors and/or cardiomyocytes, cellular lineages relevant in the corresponding disease, for future physiopathology studies and analysis of therapeutical approaches. We have characterized the effect of mutations identified in patients on the splicing, translation and folding processes of genes and protein describing several new molecular targets for therapeutic intervention, in the field of what is known as personalized genetic medicine. The group has developed a gene specific antisense RNA-based therapy for splicing defects in a number of IMD and developed a murine assay system for in vivo validation of the approach. We have established the proof-of-concept of the therapeutic use of readthrough drugs for nonsense mutation suppression in organic acidurias. For missense mutations affecting protein folding and stability novel compounds with chaperone activity have been identified as potential treatment for methylmalonic aciduria, some of which have been patented, and for congenital glycosylation defects. We are also working on the cellular processes involved in the pathophysiology of the disease such as mitochondrial dysfunction and endoplasmic reticulum stress. We have analyzed the mitochondrial dysfunction present in several diseases revealing secondary respiratory chain defects and increased ROS levels which could be targets for drugs acting on the restoration of the mitochondrial homeostasis. In addition, we are also analyzing the role of miRNA in the pathophysiology of propionic acidemia.


Relevant publications:

- Generation and characterization of a human iPSC line from a patient with propionic acidemia due to defects in the PCCA gene.
Alonso-Barroso E, Brasil S, Briso-Montiano Á, Navarrete R, Pérez-Cerdá C, Ugarte M, Pérez B,DesviatLR, Richard E.
Stem Cell Res. 2017 Aug;23:173-177.

- Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia.
Rivera-Barahona A, Fulgencio-Covián A, Pérez-Cerdá C, Ramos R, Barry MA, Ugarte M, Pérez B, Richard E,DesviatLR.
Sci Rep. 2017 Jul 18;7(1):5727.

- Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5' splice site.
Martínez-Pizarro A, Dembic M, Pérez B, Andresen BS, Desviat LR.
PLoS Genet. 2018 Apr 23;14(4):e1007360.

- New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type.
Brasil S, Briso-Montiano A, Gámez A, Underhaug J, Flydal MI, Desviat L, Merinero B, Ugarte M, Martinez A, Pérez B.
Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):640-648.

- Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria.
Richard E, Gallego-Villar L, Rivera-Barahona A, Oyarzábal A, Pérez B, Rodríguez-Pombo P, Desviat LR.
Oxid Med Cell Longev. 2018 Mar 20;2018:1246069.

- Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.
Bravo-Alonso I, Navarrete R, Arribas-Carreira L, Perona A, Abia D, Couce ML, García-Cazorla A, Morais A, Domingo R, Ramos MA, Swanson MA, Van Hove JLK, Ugarte M, Pérez B, Pérez-Cerdá C, Rodríguez-Pombo P.
Hum Mutat. 2017 Jun;38(6):678-691


Molecular Neuropathology

Astrocyte Physiology




Marta Navarrete Llinás






Research summary:

Astrocytes, classically considered as supportive cells for neurons without a direct role in brain information processing, are emerging as relevant elements in brain physiology through their ability to regulate neuronal and synaptic activity. Yet, their role in fundamental processes of brain function remains unknown.

Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Solid experimental data on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. The most remarkable property of synapses lies in their capacity to modify the efficiency with which they transmit information from one neuron to another. This property, known as synaptic plasticity, is the basis of information storage in the brain.

Until recently the plastic control of synaptic strength was thought to be an intrinsic property of the neuronal circuitry. Recent evidences, however, have demonstrated more active roles of glial cells in brain physiology than previously thought. This findings revealed that astrocytes, a major type of glial cells, may directly involved in the regulation of neuronal and synaptic function by responding to neurotransmitters released from synaptic terminals and by releasing gliotransmitters that can impact neurons and synapse (Figure 1).


Figure 1

Consequently, a novel view of the brain function has emerged in which brain physiology does not result exclusively from the neuronal network activity, this arise from the interactive activity of neuron-glial networks.

Our overall aim is to further study of the role of astroglial cells in the brain and also focus on the roles of these glial cells in disorders of the nervous system. We use state-of-the-art techniques, that include optogenetics, chemogenetics, multiphoton microscopy, combined calcium imaging and multiple electrophysiological recordings, in slices and in vivo, in transgenic and experimental animal models.

Supported by: SAF2014-58598-JIN; L´Oreal-Unesco "for woman in Science"; I Convocatoria Ayudas Fundación BBVA a Investigadores, Innovadores y Creadores Culturales.

Adult neurogenesis and neurodegenerative diseases



María Llorens-Martín






Research summary:

Our research group is focused on investigating the mechanisms that control adult hippocampal neurogenesis, both under physiological and pathological conditions. In particular, we are interested in determining the therapeutic potential of increasing adult hippocampal neurogenesis for the treatment of neurodegenerative diseases such as Alzheimer´s disease (AD) and other tauopathies. These diseases are characterized by a general loss of neural plasticity. In this regard, one of most affected areas is the hippocampus. This brain region plays a crucial role in learning and memory. Furthermore, a unique feature of this structure is the existence of adult neurogenesis. The process of adult hippocampal neurogenesis encompasses the birth and functional integration of newborn neurons throughout lifetime. This process confers and extraordinary high level of plasticity to the hippocampus. Thus, numerous strategies aim to potentiate the functionality of these newborn neurons and to counteract the loss of neural plasticity are being currently developed. We aim to understand the cellular mechanisms driving the impairment in the functional integration of newborn neurons that takes place in the brain of AD patients by using several animal models of the disease. Moreover, we are trying to find neuroprotective strategies that may prevent and/or slow down the advance of this devastating disease.



In this picture, two newborn granule neurons are shown. In red, it can be visualized the green fluorescent protein (GFP) labeling the whole dendritic structure of the newborn granule neurons. In green, the postsynaptic densities of these newborn granule neurons can be observed.





  • The Alzheimer´s Association (New Investigator Research Grant 2015-2017)
  • The Alzheimer´s Association (Alzheimer Association Research Grant 2018-2020)
  • The Association for Frontotemporal Dementia (Basic Science Pilot Grant Award 2016-2017)
  • Spanish Ministry of Economy and Competitiveness (Ramón y Cajal contract, 2017-2021)
  • Spanish Ministry of Economy and Competitiveness (Programa Estatal I+D+i orientada a los retos de la sociedad, 2018-2020)
  • Comunidad de Madrid, Programa de Garantía de Empleo Juvenil (2018-2019)



Doctoral theses:

  • Noemí Pallas Bazarra. “Study of the role of Tau protein on the modulation of adult hippocampal neurogenesis”. Universidad Autónoma de Madrid. July-2015. Mark: Summa Cum Laude. CBMSO PINP Award 2017



Current supervision of Ph.D. and M.Sc. Projects:

  • Julia Terreros-Roncal (Ph.D. student Universidad Autónoma de Madrid)
  • Elena Moreno Jiménez (Ph.D. student Universidad Autónoma de Madrid)
  • Miguel de la Flor García (M.Sc. student Universidad Autónoma de Madrid)



Selected Publications:

  • Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons. Bolós M; Pallas-Bazarra N; Terreros-Roncal J; Perea JR; Jurado-Arjona J, Ávila J; Llorens-Martín M. Translational Psychiatry.
  • Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons. Bolós M; Perea JR; Terreros-Roncal J; Pallas-Bazarra N; Jurado-Arjona J, Ávila J; Llorens-Martín M. Brain Behav Immun. 2017 Oct 7. pii: S0889-1591(17)30455-5.
  • GSK-3β overexpression alters the dendritic spines of developmentally generated granule neurons in the mouse hippocampal dentate gyrus. Pallas-Bazarra N, Kastanauskaite A, Avila J, DeFelipe J, Llorens-Martín M. Frontiers in Neuroanatomy. 2017 Mar 10;11:18.
  • Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis. Pallas-Bazarra N, Jurado-Arjona J, Navarrete M, Esteban JA, Hernández F, Ávila J, Llorens-Martín M. EMBO J. 2016 Jul 1; 35 (13) :1417 - 36.
  • Versatile use of rtTA-expressing retroviruses in the study of neurodegeneration. Teixeira CM, Ávila J, Llorens-Martín M. Oncotarget. 2016 Dec 30. doi: 10.18632/oncotarget.14386.
  • Llorens-Martín M, Fuster-Matanzo A, Teixeira CM, Jurado-Arjona J, Ulloa F, Defelipe J, Rábano A, Hernández F, Soriano E, Avila J. GSK-3β overexpression causes reversible alterations on postsynaptic densities and dendritic morphology of hippocampal granule neurons in vivo. Mol Psychiatry. 2013 Apr;18(4):451-60.

Calcium signalling in mitochondria and insulin/leptin signalling during ageing

 Lab 321 Grupo Jorgina Satrustegui 400


Jorgina Satrústegui




Research summary:

Ca2+ entry in mitochondria through the Ca2+ uniporter is important in cell Ca2+ signaling, but its persistence in mitochondria is associated with mitochondrial dysfunction and cell death. We are interested in the study of systems for Ca2+ signaling in mitochondria that do not require Ca2+ entry in the organelle: the mitochondrial carriers of aspartate-glutamate carriers (AGC) aralar and citrin, components of the malate aspartate shuttle (MAS), and those of ATP-Mg/Pi, or Short CaMCs (SCaMCs) which sense extramitochondrial Ca2+ to regulate metabolite transport and mitochondrial functionality. We focus on their role in regulating respiration in intact cells and in the regulation of brain aspartate and glutamate levels and traffic.
We found that these transporters, particularly AGC1/Aralar, are essential for basal mitochondrial respiration of intact cultured neurons and for the Ca2+ dependent stimulation of respiration in response to different workloads.

 Jorgina Satrustegui Fig01 300 ------


Mitochondrial Calcium Uniporter (MCU) and Ca2+-regulated mitochondrial carriers, SCaMCs and AGCs, mediate Ca2+-signalling to mitochondria. MCU and SCaMCs are activated by cytosolic [Ca2+] at uM range whereas that AGCs require lower cytosolic [Ca2+] about 100-300 nM for activation.


Jorgina Satrustegui Fig02 300

Representative images of WT and SCaMC-3 KO neurons transfected with the mitochondrial FRET-based ATP probe GO-ATeam-2 to monitor changes in mitochondrial ATP levels after NMDA exposure.  





The AGC1/Aralar KO mouse recapitulates many features of human AGC1 deficiency including very low levels of brain N-acetyl-aspartate, hypomyelination and seizures. We proposed that in brain, glial glutamate and glutamine synthesis requires aspartate produced in neurons, and we have now verified this proposal within the retina, finding that glutamine synthesis in Müller glial cells depends on the transcellular flux of aspartate from photoreceptors. These new functions of AGC1/Aralar-MAS in intra- and intercellular traffic of amino acids may set the basis for new therapeutic strategies in this and other brain disorders.
Aging is characterized by insulin and leptin resistance, and cardiovascular disease. We focuses our work in two aspects: 1) Changes in heart function in aged rats fed ad libitum or after 3-months of moderate caloric restriction; and 2) Changes in CCK satiating and insulin sensitizing effects looking for possible mechanisms involved in the development of insulin resistance with aging and its reversion.



  • Llorente-Folch, I., Sahún, I., Contreras, L., Casarejos, MJ., Grau JM, Saheki, T., Mena, MA., Satrústegui, J., Dierssen M. and Pardo, B. (2013) AGC1-malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway. J. Neurochem. 124, 347-362.
  • Amigo, I., Traba, J., González-Barroso, MM., Rueda, CB., Fernández, M., Rial, E., Sánchez, A, Satrústegui, J. and del Arco, A. (2013) Glucagon regulation of oxidative phosphorylation requires an increase in matrix adenine nucleotide content through Ca2+ activation of the mitochondrial ATP-Mg/Pi carrier SCaMC-3. J. Biol. Chem. 288, 7791-7802.
  • Llorente-Folch, I., Rueda, CB., Amigo, I., del Arco, A., Saheki, T., Pardo, B. and Satrústegui, J. (2013) Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. J. Neurosci. 33, 13957-13971.
  • Du, J., Cleghorn, W., Contreras, L, Linton, JD., Chan, GC., Chertov, AO., Saheki, T., Govindaraju, V., Sadilek, M., Satrústegui J, Hurley JB. (2013) Cytosolic reducing power preserves glutamate in retina. Proc. Natl. Acad. Sci. U. S. A. 110, 18501-18506.
  • Pla-Martín, D., Rueda, CB., Estela, A., Sánchez-Piris, M., González-Sánchez, P., Traba, J., de la Fuente, S., Scorrano, L., Renau-Piqueras, J., Alvarez, J., Satrústegui, J. and Palau, F. (2013) Silencing of the Charcot-Marie-Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry. Neurobiol. Dis. 55, 140-151.
    • Du J, Cleghorn WM, Contreras L, Lindsay K, Rountree AM, Chertov AO, Turner SJ, Sahaboglu A, Linton J, Sadilek M, Satrústegui J, Sweet IR, Paquet-Durand F, Hurley JB. (2013) Inhibition of mitochondrial pyruvate transport by zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina. J. Biol. Chem. 288, 36129-36140.
    • Pardo B, Contreras L, Satrústegui J. (2013) De novo Synthesis of Glial Glutamate and Glutamine in Young Mice Requires Aspartate Provided by the Neuronal Mitochondrial Aspartate-Glutamate Carrier Aralar/AGC1. Front. Endocrinol. 4, 149.
    • Rueda, CB., Llorente-Folch, I., Amigo, I., Contreras, L., González-Sánchez, P., Martínez-Valero, P., Juaristi, I., Pardo, B., del Arco, A. and Satrústegui J. (2014) Ca(2+) regulation of mitochondrial function in neurons. Biochim. Biophys. Acta 1837, 1617-1624.
    • Lindsay, KJ., Du, J., Sloat, SR., Contreras, L., Linton, JD., Turner, SJ., Sadilek, M., Satrústegui, J. and Hurley, JB. (2014) Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. Proc. Natl. Acad. Sci. U. S. A. 111, 15579-15584.
    • Granado, M., Rubio, C., Amor, S., Monge, L., Fernández, N., Carreño-Tarragona, G., Carrascosa, JM. and García-Villalón ÁL. (2014) Effects of age and caloric restriction on the cardiac and coronary response to endothelin-1 in rats. Exp. Gerontol. 60, 183-189.

    Capítulos de libros:

    del Arco, A. and Satrústegui, J. (March 2013) Mitochondrial Carriers. In: eLS. John Wiley & Sons, Ltd: Chichester.


Doctoral theses:

Ignacio Amigo de la Huerga (2013). “Characterization of SCaMC-3, the mitochondrial ATP-Mg/Pi carrier present in liver and brain”. UAM. Jorgina Satrústegui y Araceli del Arco

Irene Llorente Folch (2013). “New roles of aralar, the brain mitochondrial aspartate/glutamate carrier in dopamine handling glutamate excitotoxicity and regulation of mitocondrial respiration”. UAM. Jorgina Satrústegui y Beatriz Pardo.

Carlos B. Rueda Díez (2014). “Ca2+ modulation of mitochondrial function under physiological and pathological stimulation: Role of the ATP-Mg/Pi carrier, SCaMC-3”. UAM. Jorgina Satrústegui, Beatriz Pardo y Araceli del Arco.


Inherited Metabolic Disorders: Identification of new causative genes of disease and investigation of new therapeutic strategies





Mª Pilar Rodríguez-Pombo







Research summary:

Knowledge of genes and mutations causing pathology is becoming a key factor to understand the relationship between gene function and disease, and from there, to try to mitigate the biochemical dysfunction. This principle, which applies to any disease with a genetic basis, is especially relevant to the 30 million of Europeans suffering from a rare disease.

The widespread use of resources aimed to decipher the genetics of complex diseases has prompted an unprecedented development of technologies such as next generation sequencing (NGS), or genotyping arrays, which have allowed the identification of new genes and mutations in over 40 monogenic diseases. Nevertheless, still there are a very numerous clinical entities affecting to a small number of patients for which the deficient gene is unknown.

Our working group is currently implementing some of these methodologies for searching new genes involved in specific groups of inherited metabolic diseases classified as rare and predominantly with a neurological impact. Among those, are especially relevant various neonatal epileptic encephalopathies (glycinergic encephalopathy, Maple Syrup Disease, and several multiple mitochondrial dysfunction syndromes). We have recently reported the identification of a novel regulatory defect in the branched-chain-α-keto acid dehydrogenase responsible for the pathology of Maple Syrup Urine Disease. The second major goal of our work is focused on finding new targets and therapeutic strategies tailored to the phenotype / genotype for each specific patient. We propose two different lines of experimentation. The first one based on the analysis of the biochemical phenotype, essential to understanding the pathophysiology of the disease. The second based on the understanding of the molecular mechanism of the allelic variants identified in each patient. In this case, we will explore the applicability of therapies based on the modulation of mechanisms involved in the processing, stability or translation of mRNA. The ultimate goal will be to offer a personalized treatment option, adapted to the phenotype/genotype of each patient.


Role of R-Ras1 and R-Ras2 in myelination processes



Beatriz Cubelos Álvarez




Research summary:

GTPases from the R-Ras subfamily are involved in celular proliferation and differentiation. Alterations in myelin synthesis produce a decrease in the myelin sheath wrapping the axons modifying their conduction capability and causing important illnesses such as Multiple Sclerosis, optic neuromyelitis and hypomyelinating leukodystrophies (ELA) among others. Demyelinating diseases present a moderate-high prevalence, presenting 60 cases each 100.000 inhabitants, this implies that in Spain more than 50.000 people suffer this kind of pathologies. Establishing the molecular bases implicated in mielination constitutes an important target for our research group.

In our laboratory we investigate the role that R-Ras subfamily members play in the regulation of differentiation and survival processes of oligodendrocytes through PI3K/AKT molecular pathway.

This Project has been financiated by the Economy, Industry and Competitivity Minister. 


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Translational medicine in inborn errors of metabolism and other rare genetic diseases





Belén Pérez González






Research summary:

Inborn errors of metabolism (IEM) are a large group of rare genetic diseases, including any condition in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Nevertheless many of them detected by standard biochemical test are not genetically solved. In addition, many of them lack a definitive therapy. In this context, our objectives, aligned with the worldwide aims in translational research in rare diseases, are addressed to improve the knowledge of IEM towards tailored treatments. First, our activity is aimed to the identification of new genes causing pathology using a combination of "omics" tools (genomic, transcriptomic and metabolomic technologies) and cellular biology techniques, in order to decipher the effect of altered genes and to identify novel pathological processes. Specifically, we are working on the identification and characterization of genetic defects involved in the process of glycosylation and protein transport (CDG syndrome), as well as in other diseases related to mitochondrial dysfunction or neurological disorders due to cerebral glucose transport deficiency, among others. We are also involved in the development of specific therapeutic strategies targeted to the mechanism of action of the mutations detected in neurometabolic diseases in the era of the personalized medicine. To that end, we are specifically involved in the development of therapies designed to rescue defects affecting protein folding, an extended mechanism in many IEM. For preclinical studies and for searching additional therapeutic targets based on pathophysiology studies we are working in the generation of disease cellular models obtained from reprogramming of patient derived fibroblasts and subsequent differentiation into hepatocytes, neurons or other tissues more relevant to the disease. In a later preclinical stage we intend also to use hepatic and cerebellar organoids to validate the potential drugs before testing in the adequate animal models.

This project is funded by the following grants: ISCIII (PI16/00573), CIBERER (ER18TRL746), Comunidad de Madrid (B2017/BMD3721) y Fundación Isabel Gemio in collaboration with La Obra Social de la Caixa (LCF/PR/PR16/11110018).

Logos Financiación

Relevant publications:

  • New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type. BBA, Molecular Basis of Disease(2018) 1864(2):640-648.
  • Generation and characterization of two human iPSC lines from patients with methylmalonic acidemia cblB type. Stem Cell Research (2018) 29:143-147.
  • Protein misfolding diseases: prospects of pharmacological treatment. Clin Genet. 2017 Jul 3. doi: 10.1111/cge.13088. Review.
  • A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis. J Pediatr. 2017 Apr;183:170-177.
  • Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease. Hum Mutat. 2017 Jun;38(6):678-691. doi: 10.1002/humu.23208. Epub 2017 Mar 20.
  • Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG. Hum Mutat. 2017 Feb;38(2):160-168. doi: 10.1002/humu.23138. Epub 2016 Nov 21.
  • Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing. Genet Med. 2016 Oct;18(10):1037-43. doi: 10.1038/gim.2015.217.
  • Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1862 (4), pp. 592-600.
  • Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II. Biochim Biophys Acta. 2015 Dec;1852(12):2712-21. doi: 10.1016/j.bbadis.2015.09.011. Epub 2015 Sep 25.
  • The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein.Hum Mutat. Hum Mutat. 2015 Sep;36(9):851-60. doi: 10.1002/humu.22817.

Molecular pathways to Neurodegeneration. Cellular and Animal Models: Role of post-translational modification of Tau in its degradation by calpains





Félix Hernández







Research summary:

--------- Fig01-300 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.

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 -sulting 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.


Genetic bases of Alzheimer's Disease: Genomic study of pathogenic cell models



María Jesús Bullido




Research summary:

In the last years our group has focused on the search of risk factors and/or genes involved in the Alzheimers disease (AD), developing cellular models to obtain candidates that are then validated through genetic association studies in patients. One of the main objectives of the group is to establish the involvement in the pathogenesis of AD of two factors associated with aging, oxidative stress (OS) and infection by HSV 1.

-------- Fig01-300
  Oxidative stress produces the accumulation of APP protein and its carboxi and amino terminal fragments in SK N MC neuronal cells.

We have found that in the cell models OS regulates the traffic, degradation and proteolytic processing of the peptide Aβ precursor protein (APP), and that this regulation involves the two main cellular proteolytic systems: ubiquitin/proteasome and autophagy/lysosome. On the other hand, HSV-1 is able to reproduce most of the anomalies found in the brains of AD patients, as the hyperphosphorylation of tau protein and alterations of the autophagic process that lead to the intracellular accumulation of Aβ; these effects are increased in the presence of OS.
After the genomic analysis of the cell models, we have focused on the list of genes which expression is modulated by HSV 1 in the presence of OS because this is similar to the infection in aged people for their functional validation and genetic risk association studies. The "cytokine-mediated inflammation" function is highly enriched in this list, which is consistent with the findings of the latest genome wide association studies (GWAs) and suggests that HSV 1 may participate in the pathogenesis of sporadic AD.

Other works of the group during this period include the analysis of cellular models of monogenic AD, and the participation in collaborative genetic association studies, mainly with groups of CIBERNED and as part of the European consortium EADI, which are revealing novel AD risk factors..



  • Kristen H, Sastre I, Muñoz-Galdeano T, Recuero M,Aldudo J, Bullido MJ (2018) The lysosome system is severely impaired in a cellular model of neurodegeneration induced by HSV-1 and oxidative stress. Neurobiol Aging 68: 5-17.
    Kristen H, Santana S, Sastre I, Recuero M, Bullido MJ, Aldudo J (2015) Herpes simplex virus type 2 infection induces AD-like neurodegeneration markers in human neuroblastoma cells. Neurobiol Aging 36(10): 2737-2747.
  • Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW et al. Bullido MJ (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49(9):1373-1384.
  • Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, Letenneur L, Lövheim H, Mancuso R, Miklossy J, Otth C, Palamara AT, Perry G, Preston C, Pretorius E, Strandberg T, Tabet N, Taylor-Robinson SD, Whittum-Hudson JA (2016) Microbes and Alzheimer's Disease. J Alzheimers Dis 51(4): 979-84.
  • Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, et al. (2016) Microbes and Alzheimer's disease. J Alzheimers Dis 51(4): 979-984.
  • Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, et al. Bullido MJ. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21(1): 108-17.
  • Pastor P, Moreno F, Clarimón J, Ruiz A, Combarros O, Calero M, De Munain AL, Bullido MJ, et al (2015). MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE ε 4 noncarriers: Results from the dementia genetics Spanish consortium. J Alzheimers Dis 49(2): 343-352.
  • Jones L, Lambert JC, Wang LS, Choi SH, Harold D, Vedernikov A, et al. Bullido MJ (2015) Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimers & Dementia 11(6): 658-671.
  • Ruiz A, Dols-Icardo O, Bullido MJ, Pastor P, Rodríguez-Rodríguez E, et al. (2014) Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia. Neurobiol Aging 35: 444 e1-4.
  • Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, et al. (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45: 1452-8.
  • Santana S, Sastre I, Recuero M, Bullido MJ, Aldudo J (2013) Oxidative stress enhances neurodegeneration markers induced by herpes simplex virus type 1 infection in human neuroblastoma cells. PLoS One 8: e75842.
  • Recuero M, Munive VA, Sastre I, Aldudo J, Valdivieso F, et al. (2013) A free radical-generating system regulates AbetaPP metabolism/processing: involvement of the ubiquitin/proteasome and autophagy/lysosome pathways. J Alzheimers Dis 34: 637-647.
  • Santana S, Recuero M, Bullido MJ, Valdivieso F, Aldudo J (2012) Herpes simplex virus type I induces the accumulation of intracellular beta-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. Neurobiol Aging 33: 430 e419-433.
  • Santana S, Bullido MJ, Recuero M, Valdivieso F, Aldudo J (2012) Herpes simplex virus type I induces an incomplete autophagic response in human neuroblastoma cells. J Alzheimers Dis 30: 815-831.
  • Recuero M, Munoz T, Aldudo J, Subias M, Bullido MJ, et al. (2010) A free radical-generating system regulates APP metabolism/processing. FEBS Lett 584: 4611-4618.
  • Recuero M, Vicente MC, Martinez-Garcia A, Ramos MC, Carmona-Saez P, et al. (2009) A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease. Aging Cell 8: 128-139.




- Fundación Madrid+D. Premio a las mejores patentes; accésit. (2011)
- Sociedad Madrileña de Neurología. Premio Ramón y Cajal de Investigación básica (2011)

Molecular mechanisms of neuronal differentiation and regeneration

2016 12 14 Grupo F Wandosell 07


Francisco Wandosell




Research summary:

Our group, "Molecular mechanisms of Neurodegeneration and Regeneration ", is a line established in the CBM over several years. We are interested in the analysis of the molecular mechanisms fired by processes neurodegenerative, trying to understand the key points of these processes; for a second attempt to design new regenerative alternatives, or to propose new therapeutic targets.


First, our studies of molecular mechanisms of degeneration are focused on the role of Pi3K-Akt: GSK3 in neurodegeneration We have seen that some neuroprotective elements as estradiol modulates elements, such as GSK3 and β-catenin, proteins shared by other signaling pathways like Wnt. And we recently demonstrate that estradiol may trigger Akt-mTORC1 pathway. All these data represent a new signalling pathway, triggered by estradiol that would complement to IGF-1 and Wnt. These findings have led us to extend the analysis of signalling mediated by Estradiol in normal neuronal physiology and in some pathological conditions such as Ischemia model.

Second and complementary we are interested in the molecular mechanisms that regulate the generation and maintenance of the axonal polarity. This morphological polarity appears during development when the neuron differentiates and begins to extend an axon. Subsequently they "mature" and form their initial segment of the axon. Studies of several laboratories, including ours have shown that PI3K-kinase activity allows axonal growth and determining axonal polarity (in collaboration with JJ. Garrido´s group from Cajal Inst.). Our laboratory has helped identify some of the elements that control polarity, such that GSK3, control the polarity. Our work, in this field, will follow to identify upstream and downstream elements that would be essential for this "morphogenetic process".







In summary, we are focusing on track PI3K-Akt signalling and elements than those elements that control neuron morphogenesis and are modified in pathology.



    • ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals. Ordóñez-Gutiérrez L, Posado-Fernández A, Ahmadvand D, Lettiero B, Wu L, Antón M, Flores O, Moghimi SM, Wandosell F. Biomaterials. 2017 Jan;112:141-152.
    • WIP Drives Tumor Progression through YAP/TAZ-Dependent Autonomous Cell Growth. Gargini R, Escoll M, García E, García-Escudero R, Wandosell F, Antón IM. Cell Rep. 2016 Nov 15;17(8):1962-1977.
    • Class I PI3-kinase or Akt inhibition do not impair axonal polarization, but slow down axonal elongation. Diez H, Benitez MJ, Fernandez S, Torres-Aleman I, Garrido JJ, Wandosell F. Biochim Biophys Acta. 2016 Nov;1863(11):2574-2583.
    • AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging. Ordoñez-Gutierrez L, Fernandez-Perez I, Herrera JL, Anton M, Benito-Cuesta I, Wandosell F. J Alzheimers Dis. 2016 Sep 6;54(2):645-56.
    • Secreted herpes simplex virus-2 glycoprotein G alters thermal pain sensitivity by modifying NGF effects on TRPV1. Cabrera JR, Viejo-Borbolla A, Alcamí A, Wandosell F. J Neuroinflammation. 2016 Aug 30;13(1):210.
    • Reticulon-4B/Nogo-B acts as a molecular linker between microtubules and actin cytoskeleton in vascular smooth muscle cells. Rodríguez-Feo JA, Gallego-Delgado J, Puerto M, Wandosell F, Osende J. Biochim Biophys Acta. 2016 Aug;1863(8):1985-95.
    • Angiotensin II type-2 receptor stimulation induces neuronal VEGF synthesis after cerebral ischemia. Mateos L, Perez-Alvarez MJ, Wandosell F.
    • Biochim Biophys Acta. 2016 Jul;1862(7):1297-308.
    • Oncogene-mediated tumor transformation sensitizes cells to autophagy induction. Gargini R, García-Escudero V, Izquierdo M, Wandosell F. Oncol Rep. 2016 Jun;35(6):3689-95.
    • PTEN recruitment controls synaptic and cognitive function in Alzheimer's models. Knafo S, Sánchez-Puelles C, Palomer E, Delgado I, Draffin JE, Mingo J, Wahle T, Kaleka K, Mou L, Pereda-Perez I, Klosi E, Faber EB, Chapman HM, Lozano-Montes L, Ortega-Molina A, Ordóñez-Gutiérrez L, Wandosell F, Viña J, Dotti CG, Hall RA, Pulido R, Gerges NZ, Chan AM, Spaller MR, Serrano M, Venero C, Esteban JA. Nat Neurosci. 2016 Mar;19(3):443-53.
    • Stroke and Neuroinflamation: Role of Sexual Hormones. Perez-Alvarez MJ, Wandosell F. Curr Pharm Des. 2016;22(10):1334-49. 
    • The hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease. Mancini S, Minniti S, Gregori M, Sancini G, Cagnotto A, Couraud PO, Ordóñez-Gutiérrez L, Wandosell F, Salmona M, Re F. Nanomedicine. 2016 Jan;12(1):43-52

Other activities:

- Master in Genetic and Cellular Biology (UAM and UAH ). Drª. Rosa Sacedon y Drª Marta Torroba. Department of Cellular Biology. UCM

- Master in Molecular and Cellular Biology. Department of Molecular Biology and Department of Biochemistry. UAM. Drª. Inés Antón (CNB) and Drª . Margarita Cervera (UAM)

- Master in Molecular Biomedicine. Department of Molecular Biology and Biochemistry (UAM). Dr. Javier Díaz Nido (Dpt. Molecular Biology, UAM) and Dr. Francisco Wandosell (CBMSO, CSIC-UAM).

This group is also part of the Centre for biomedical research in neurodegenerative diseases network (CiberNed):

Industry collaboration:
- Allinky S. L. (2015-2016)

Doctoral theses:

Maribel Escoll (2015).

Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration



Alberto Martínez Serrano




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 diseases, pharmaceutical drugs are useful at early stages of the disease, but 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 acquires special relevance, with the prospect that healthy stem cell derivatives, after implantation, would either delay disease progression or actually cure the disease.

Our research group is interested in understanding basic self-renewal (niche factors) and developmental events leading to maturation of stem cell derivatives, using: 1) Neural stem cells, obtained from foetal or adult human tissue, and thus 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 derived; and 3) Induced pluripotent stem cells (iPSCs), reprogrammed from somatic adult cells.

Fig01-300 ..... Generation of human dopaminergic neurons from neural stem cells.
Top panels are microphotographs of human neurons generated in culture, stained for a general neuronal marker (ß-III-tubulin, green) and Tyrosine Hydroxylase (dopaminergic marker, red). The lower panel is a merge of the two photographs, highlighting in yellow the presence of human dopaminergic neurons.

Our main research focus is thus on basic cell growth and developmental events involved in the generation of mature cells, particularly of Dopaminergic neurons, to learn how to harness the potential that stem cells may have for therapy of these devastating diseases.

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. To this end we are implementing the technology of zinc-finger nucleases, to help to conduct homologous recombination. Last, we are developing nanotools to label and track the cells in vivo, and study their cell biology in culture.

Relevant publications:

  • Daviaud N, Garbayo E, Sindji L, Martínez-Serrano A, Schiller PC, Montero-Menei CN. Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease. Stem Cells Transl Med. 2015 Jun;4(6):670-84. doi: 10.5966/sctm.2014-0139. Epub 2015 Apr 29. PMID:25890124
  • Ramos-Gómez M, Seiz EG, Martínez-Serrano A. Optimization of the magnetic labeling of human neural stem cells and MRI visualization in the hemiparkinsonian rat brain. J Nanobiotechnology. 2015 Mar 5;13:20. doi: 10.1186/s12951-015-0078-4. PMID:25890124
  • González-Sánchez HM, Monsiváis-Urenda A, Salazar-Aldrete CA, Hernández-Salinas A, Noyola DE, Jiménez-Capdeville ME, Martínez-Serrano A, Castillo CG. Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state. J Neurovirol. 2015 Apr 8. [Epub ahead of print] PMID:25851778
  • Pino-Barrio MJ, García-García E, Menéndez P, Martínez-Serrano A. V-myc immortalizes human neural stem cells in the absence of pluripotency-associated traits. PLoS One. 2015 Mar 12;10(3):e0118499. doi: 10.1371/journal.pone.0118499. eCollection 2015. PMID:25764185
  • Martínez-Serrano A, Castillo CG, Courtois ET, García-García and Liste I (2011) Modulation of the generation of dopaminergic neurons from human neural stem cells by Bcl-XL. Mechanisms of action. Vitam. Horm. 87, 175-205.
  • García-García, E., Pino-Barrio, M.J., López-Medina, L., and Martínez-Serrano, A. (2012) Intermidiate progenitors are increased by lengthening of cell cycle through calcium signalling and p53 expression in human neural progenitors. Mol. Biol. Cell., 23, 1167-1180.
  • Fernández-Cabada, T., Sánchez-López de Pablo, C., Martínez-Serrano, A., del Pozo Guerrero, F. Serrano-Olmedo, J.J., Ramos-Gomez M (2012) Cell death induction in glioblastoma cell lines by hyperthermic therapy based on gold nanorods. International Journal of Nanomedicine 7, 1511-1523.
  • Ramos-Moreno, T., Castillo, C.G. and Martínez-Serrano, A. (2012) Long-term behavioral effects of functional dopaminergic neurons generated from human neural stem cells in the rat 6-OH-DA Parkinson's disease model. Effects of the forced expression of Bcl-XL. Behav. Brain Res., 232, 225-232.
  • Seiz, E.G., Ramos-Gómez, M., Courtois, E.T., Tønnesen, J., Kokaia, M., Liste I., and Martínez-Serrano, A., (2012) Human midbrain precursors activate the expected developmental genetic program and differentiate to functional A9 dopamine neurons in vitro. Short and Long term enhancement by Bcl-XL. Experimental Cell Research 318: 2446-59.


Doctoral theses:

Javier Gonzalez Lendínez (2011). Identification and analysis of suitable human ventral mesencephalic precursors of dopaminergic neurons for cell therapy research in Parkinson's Disease. Universidad Autónoma de Madrid. Co-director: Dra. Tania Ramos Moreno.

Emma Green (2012). The use of zinc-finger nucleases to track the generation of dopaminergic neurons from immortalised human ventral mesencephalic neural stem cells. Universidad de Keele. Co-directores: Alberto Martínez Serrano y Tania Ramos Moreno.

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