CENTRO DE BIOLOGÍA MOLECULAR SEVERO OCHOACaptura de pantalla 2022 09 14 a las 10.27.10    

Molecular mechanisms of Oligodendrocyte-Neuron interaction & pathologies associated with myelin

Research summary:

In our laboratory we study the neurological component of demyelinating pathologies and investigate the molecular mechanisms responsible for the processes of myelination in the Central Nervous System (CNS). Adequate myelination is essential for the correct transmission of the nerve impulse. In the CNS, oligodendrocytes are the cells responsible for myelination of neuronal axons, through a complex process that requires complex cellular interactions. In the absence of a correct myelination, diseases such as Multiple Sclerosis or leukodystrophies appear, currently orphans of an effective treatment. The possibility of generating therapies based on the neurological component of these diseases could stimulate the regeneration of new oligodendrocytes or increase the capacity of the remaining set of oligodendrocytes to produce more myelin and reestablish correct myelination. Our group has demonstrated the importance of the GTPases R-Ras1 and R-Ras2, essential proteins in the differentiation and survival of OLs. Moreover, we have described to the relevance of their presence for the maintenance of energetic homeostasis and for the correct functioning of the nerve impulse transmission. Models lacking R-Ras1 and/or R-Ras2 faithfully reproduce the symptomatological characteristics of myelin diseases and could be used as models for the development of new treatments based on the neurological component.

Image

Figure 1.

(a) Loss of oligodendrocytes in mutant mice lacking from R-Ras1, R-Ras2, or both. (b) Axons lose their protective myelin sheath when they lack R-Ras1 and/or R-Ras2. (c) and (d) Loss of visual function generated by the loss of oligodendrocytes and myelin in the mutant mice.

Image


* For external calls please dial 34 91196 followed by the extension number
Last nameNameLaboratoryExt.*e-mailProfessional category
Alcalá MorotePablo3054650Estudiante TFM
Alcover SánchezBerta3054650berta.alcover(at)cbm.csic.esTitulado Sup.de Actividades Técn. y Profes. GP1
Cubelos AlvarezBeatriz3054650bcubelos(at)cbm.csic.esProfesor Titular Universidad, GA

Relevant publications:

  • Garcia-Martin G., Sanz-Rodriguez M., Alcover-Sanchez B., Pereira MP., Wandosell F., Cubelos B. R-Ras1 and R-Ras2 Expression in Anatomical Regions and Cell Types of the Central Nervous System. Int J Mol Sci. 2022 Jan 17;23(2):978. doi: 10.3390/ijms23020978. PMID: 35055164. (IJMS, IF: 5.92).
  • Garcia-Martin G., Alcover-Sanchez B., Wandosell F., Cubelos B. “Pathways involved in remyelination after cerebral ischemia”. Curr Neuropharmacol. 2021 Jun 9. doi: 10.2174/1570159X19666210610093658. Epub ahead of print. PMID: 34151767. (Curr Neuropharmacol., IF: 4.66).
  • Alcover-Sanchez B, Garcia-Martin G, Escudero-Ramirez J, Gonzalez-Riano C, Lorenzo P, Gimenez-Cassina A, Formentini L, de la Villa-Polo P, Pereira MP, Wandosell F, Cubelos B. Absence of R-Ras1 and R-Ras2 causes mitochondrial alterations that trigger axonal degeneration in a hypomyelinating disease model. Glia. 2021 Mar;69(3):619-637. doi: 10.1002/glia.23917. Epub 2020 Oct 3. PMID: 33010069.
  • Alcover-Sanchez B, Garcia-Martin G, Wandosell F, Cubelos B. R-Ras GTPases Signaling Role in Myelin Neurodegenerative Diseases. Int J Mol Sci. 2020 Aug 17;21(16):5911. doi: 10.3390/ijms21165911. PMID: 32824627; PMCID: PMC7460555.
  • Sanz-Rodriguez M, Gruart A, Escudero-Ramirez J, de Castro F, Delgado-García JM, Wandosell F, Cubelos B. R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System. J Neurosci. 2018 May 30;38(22):5096-5110. doi: 10.1523/JNEUROSCI.3364-17.2018. Epub 2018 May 2. PMID: 29720552; PMCID: PMC6705947.
  • Gonzalez-Riano C, Sanz-Rodríguez M, Escudero-Ramirez J, Lorenzo MP, Barbas C, Cubelos B, Garcia A. Target and untargeted GC-MS based metabolomic study of mouse optic nerve and its potential in the study of neurological visual diseases. J Pharm Biomed Anal. 2018 May 10;153:44-56. doi: 10.1016/j.jpba.2018.02.015. Epub 2018 Feb 10. PMID: 29459235.
  • Doan RN, Bae BI, Cubelos B, Chang C, Hossain AA, Al-Saad S, Mukaddes NM, Oner O, Al-Saffar M, Balkhy S, Gascon GG; Homozygosity Mapping Consortium for Autism, Nieto M, Walsh CA. Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Cell. 2016 Oct 6;167(2):341-354.e12. doi: 10.1016/j.cell.2016.08.071. Epub 2016 Sep 22. PMID: 27667684; PMCID: PMC5063026.
  • Cubelos B, Briz CG, Esteban-Ortega GM, Nieto M. Cux1 and Cux2 selectively target basal and apical dendritic compartments of layer II-III cortical neurons. Dev Neurobiol. 2015 Feb;75(2):163-72. doi: 10.1002/dneu.22215. Epub 2014 Jul 30. PMID: 25059644.
  • Gutierrez-Erlandsson S, Herrero-Vidal P, Fernandez-Alfara M, Hernandez-Garcia S, Gonzalo-Flores S, Mudarra-Rubio A, Fresno M, Cubelos B. R-RAS2 overexpression in tumors of the human central nervous system. Mol Cancer. 2013 Oct 23;12(1):127. doi: 10.1186/1476-4598-12-127. PMID: 24148564; PMCID: PMC3900289.
  • Merino JJ, Bellver-Landete V, Oset-Gasque MJ, Cubelos B. CXCR4/CXCR7 molecular involvement in neuronal and neural progenitor migration: focus in CNS repair. J Cell Physiol. 2015 Jan;230(1):27-42. doi: 10.1002/jcp.24695. PMID: 24913264.
  • Cubelos B, Leite C, Giménez C, Zafra F. Localization of the glycine transporter GLYT1 in glutamatergic synaptic vesicles. Neurochem Int. 2014 Jul;73:204-10. doi: 10.1016/j.neuint.2013.09.002. Epub 2013 Sep 11. PMID: 24036061.
  • Rodríguez-Tornos FM, San Aniceto I, Cubelos B, Nieto M. Enrichment of conserved synaptic activity-responsive element in neuronal genes predicts a coordinated response of MEF2, CREB and SRF. PLoS One. 2013;8(1):e53848. doi: 10.1371/journal.pone.0053848. Epub 2013 Jan 31. PMID: 23382855; PMCID: PMC3561385.
  • Cubelos B, Nieto M. Intrinsic programs regulating dendrites and synapses in the upper layer neurons of the cortex. Commun Integr Biol. 2010 Nov;3(6):483-6. doi: 10.4161/cib.3.6.12755. Epub 2010 Nov 1. PMID: 21331220; PMCID: PMC3038044.
  • Cubelos B, Sebastián-Serrano A, Beccari L, Calcagnotto ME, Cisneros E, Kim S, Dopazo A, Alvarez-Dolado M, Redondo JM, Bovolenta P, Walsh CA, Nieto M. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex. 2010 May 27;66(4):523-35. doi: 10.1016/j.neuron.2010.04.038. PMID: 20510857; PMCID: PMC2894581.
  • Delgado P, Cubelos B, Calleja E, Martínez-Martín N, Ciprés A, Mérida I, Bellas C, Bustelo XR, Alarcón B. Essential function for the GTPase TC21 in homeostatic antigen receptor signaling. Nat Immunol. 2009 Aug;10(8):880-8. doi: 10.1038/ni.1749. Epub 2009 Jun 28. PMID: 19561613.
  • Cubelos B, Sebastián-Serrano A, Kim S, Redondo JM, Walsh C, Nieto M. Cux-1 and Cux-2 control the development of Reelin expressing cortical interneurons. Dev Neurobiol. 2008 Jun;68(7):917-25. doi: 10.1002/dneu.20626. PMID: 18327765; PMCID: PMC2938960.
  • Cubelos B, Sebastián-Serrano A, Kim S, Moreno-Ortiz C, Redondo JM, Walsh CA, Nieto M. Cux-2 controls the proliferation of neuronal intermediate precursors of the cortical subventricular zone. Cereb Cortex. 2008 Aug;18(8):1758-70. doi: 10.1093/cercor/bhm199. Epub 2007 Nov 21. PMID: 18033766.
  • González-González IM, García-Tardón N, Cubelos B, Giménez C, Zafra F. The glutamate transporter GLT1b interacts with the scaffold protein PSD-95. J Neurochem. 2008 Jun;105(5):1834-48. doi: 10.1111/j.1471-4159.2008.05281.x. Epub 2008 Feb 4. PMID: 18248606.
  • Fernández-Sánchez E, Díez-Guerra FJ, Cubelos B, Giménez C, Zafra F. Mechanisms of endoplasmic-reticulum export of glycine transporter-1 (GLYT1). Biochem J. 2008 Feb 1;409(3):669-81. doi: 10.1042/BJ20070533. PMID: 17919119.
  • Cubelos B, Giménez C, Zafra F. Localization of the GLYT1 glycine transporter at glutamatergic synapses in the rat brain. Cereb Cortex. 2005 Apr;15(4):448-59. doi: 10.1093/cercor/bhh147. PMID: 15749988.
  • Cubelos B, González-González IM, Giménez C, Zafra F. The scaffolding protein PSD-95 interacts with the glycine transporter GLYT1 and impairs its internalization. J Neurochem. 2005 Nov;95(4):1047-58. doi: 10.1111/j.1471-4159.2005.03438.x. PMID: 16271045.
  • Cubelos B, Giménez C, Zafra F. The glycine transporter GLYT1 interacts with Sec3, a component of the exocyst complex. 2005 Nov;49(6):935-44. doi: 10.1016/j.neuropharm.2005.07.021. Epub 2005 Sep 21. PMID: 16181645.
  • González-González IM, Cubelos B, Giménez C, Zafra F. Immunohistochemical localization of the amino acid transporter SNAT2 in the rat brain. 2005;130(1):61-73. doi: 10.1016/j.neuroscience.2004.09.023. PMID: 15561425.
  • Cubelos B, Gonzalez-Gonzalez I, Gimenez C and Zafra F. The amino acid transporter SN2 (SLC38A5) localizes to glial in the rat brain. Glia 2004; 49(2): 230-244
  • Nogal ML, González de Buitrago G, Rodríguez C, Cubelos B, Carrascosa AL, Salas ML, Revilla Y. African swine fever virus IAP homologue inhibits caspase activation and promotes cell survival in mammalian cells. J Virol. 2001 Mar;75(6):2535-43. doi: 10.1128/JVI.75.6.2535-2543.2001. PMID: 11222676; PMCID: PMC115875.
  • Cubelos B, Gimenéz C y Zafra F. Hipótesis glutamatérgica de la esquizofrenia: Mecanismos moleculares del transporte de glicina en las sinapsis glutamatérgicas.Real Academia Nacional Farmacia Volumen:Nº41; 5-25. ISSN 0034-0618

Tesis doctorales:

  • Berta Alcover Sánchez (Estudiante de Doctorado. Universidad Autónoma de Madrid) en curso.
  • Gonzalo García Martín (Estudiante de Doctorado. Universidad Autónoma de Madrid) en curso.
  • Brian Ernie Quinones (Estudiante de Doctorado. Universidad Autónoma de Madrid) en curso.
  • Miriam Sanz Rodríguez. Tesis doctoral: “Papel de R-Ras1 y R-Ras2 en los procesos de mielinización del SNC”. Universidad Autónoma de Madrid. Junio 2018. Calificación: Sobresaliente “Cum Laude”.

Trabajos de fin de grado y máster:

  • Rosa Plaza Clavero (Estudiante de Máster. Universidad Autónoma de Madrid) en curso.
  • Gonzalo García Martín. Trabajo de Fin de Máster: “Role of R-Ras on the Oligodendrocyte actin cytoskeleton”. Universidad Autónoma de Madrid 2021.
  • Jorge Navarro Nadal. Trabajo de Fin de Máster. Universidad Complutense de Madrid 2021.
  • Juan Escudero Ramírez. Trabajo de Fin de Máster: “Papel de RRas1 y RRas2 en la función mitocondrial del SNC”. Universidad Autónoma de Madrid. 2019.
  • Juan Ramón Perea Úbeda-Portugués. Trabajo de Fin de Máster: “Papel de RRas2 en los procesos de mielinización en el nervio óptico”. Autónoma de Madrid. 2015. Premio Especial de la Fundación ONCE al mejor trabajo de investigación curso 2014/ 2015. Accésit en el Certamen Arquímedes al mejor trabajo original de investigación. BOE Núm. 289; 3 de diciembre de 2015.
  • Andrea Alcaraz Ramírez (Estudiante de Grado. Universidad Autónoma de Madrid) en curso.
  • Gonzalo García Martín. Trabajo de Fin de Grado: “El déficit de mielina desencadena degeneración axonal en un modelo de ratón hipomielinizante”. Universidad Autónoma de Madrid. 2020.
  • Germán Benito Vicente. Trabajo de Fin de Grado: “Estudio de la contribución de R-Ras1 y R-Ras2 en la morfología oligodendrocitaria”. Universidad Autónoma de Madrid. 2019.
  • Juan Escudero Ramírez. Trabajo de Fin de Grado: “Papel de RRas1 y RRas2 en el Sistema Nervioso”. Universidad Autónoma de Madrid. 2017.
  • Manuel Troncoso. Trabajo de Fin de Grado: “Papel de RRas1 y RRas2 la mielinización del nervio óptico de ratones”. Universidad Autónoma de Madrid. 2017.
  • Pedro Herrero Vidal. Trabajo de Fin de Grado: “Papel de RRas2 en el desarrollo y función de la retina”. Universidad Autónoma de Madrid. 2014.
  • Juan Ramón Perea Úbeda-Portugués. Trabajo de Fin de Grado: “Papel de RRas2 la función de la retina”. Universidad Autónoma de Madrid. 2013.
  • Raquel Forcén García. Trabajo de Fin de Grado: “Papel de RRas2 en el desarrollo de la retina”. Universidad Autónoma de Madrid. 2013.
  • Raquel Martín Morales. Trabajo de Fin de Grado: “Papel de RRas2 en el sistema nervioso”. Universidad Autónoma de Madrid. 2012.

NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand

COOKIES POLICY

What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

  • Accept cookies: if the user presses the acceptance button, this warning will not be displayed again when accessing any page of the portal.
  • Review the cookies policy: the user can access to this page in which the use of cookies is detailed, as well as links to modify the browser settings.

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers:

fondosocialeuropeo-300px.png
Ministerio-de-Ciencia-e-Innovacin-600px.png
Comunidad-de-Madrid-600Bpx.png
agenda20-30-600px.png
fundacion-areces600px0710.png
LOGO_ERC.jpg
hrexcellence.jpg
worldwidecancerresearch-600px0710.png
aecc-600tpx.png
bbva-fund-400.png
Niemann-Pick-400px.png
wilderfund-400px.png
AliciaKoplowitz-400px.png
la-caixa-fund-600px.png
inocente-inocente-600px.png
cure-alzheimers-fund-600px.png
citrin-foundation.png
tatiana-fund02-600bpx1.png
campus-excelencia-600x400px.png
fundacion-uno-entre-cien-mil-v02.png