Molecular mechanisms of neurodegeneration
Research summary:
Our group is mostly interested in neurodegenerative disorders is now focusing in a group of brain disorders associated with aging, such as Alzheimer, disease and some type of brain tumours. A question that remains open is... are there common molecular mechanisms that underlie the age dependence of various disorders? Data from different animal models strongly support that idea that the PI3K-Akt pathway is deregulated in several brain pathologies.
With respect to AD, our previous work has led us to analyze some elements regulated by Akt, such as mTORC1. This protein complex controls general aspects of protein synthesis and autophagy; while his dysfunction has been considering a key factor in the generation and / or degradation of beta amyloid in Alzheimer's disease (AD). We are analyzing how the activity of mTORC1 modulates macro-autophagy, and how it modulates the generation of amyloid peptide in transgenic models of AD.
With regard to astrocyte-astrocytoma-gliomas tumor transformation, we have defined a new route of tumor progression and maintenance of stem-tumor phenotype, via Akt, WIP and YAP / TAZ that regulate this conversion [Collaboration: F. Wandosell (CBM) &. Dr. I. Anton (CNB)]. In addition, in both pathologies we are interested in defining new therapeutic targets and analyzing new compounds with therapeutic potential.
The last year (2016) Drª: Beatriz Cubelos (RyC/ Assist. Prof) has been incorporated as Project Leader in our lab, and is currently analyzing the phenotype of RRas1 and RRas 2 knockout mice, which among other anomalous features have defect in myelination and a deficient signaling in Akt. We have initiated a collaborative work analyzing the defective mechanism/s in both RRas mutants.
Drª B. Cubelos’ group demonstrate that R-Ras1 and R-Ras2 play essential roles in regulating myelination “in vivo” and control fundamental aspects of oligodendrocyte (OL) survival and differentiation through synergistic activation of PI3K/Akt and Erk1/2-MAPK signaling. Mice lacking R-Ras1 and/or R-Ras2 show a diminished OL population with a higher proportion of immature OLs, explaining the observed hypomyelination and provoking a slower conduction velocity of nerve impulses in main CNS tracts. She is now an independent group and you can check the specific information on their website.
Figure 1.
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| García Juan | Marta | 206 | 4591 | martagajuan(at)cbm.csic.es | Titulado Sup. Actividades Tecn. y Prof.GP1 |
| Orantes Fernández | Alba | 213 | 4425 | alba.orantes(at)cbm.csic.es | Titulado Sup. Actividades Tecn. y Prof.GP1 |
| Pérez Alvarez | María José | 206 | 4591 | Profesor Contratado Doctor Universidad, GA | |
| Rivas Muñoz | Sergio | 213 | 4591 | sergio.rivas(at)cbm.csic.es | Contratado CIBER |
| Villa González | Mario | 206 | 4591 | mario.villa(at)cbm.csic.es | Titulado Sup.de Actividades Técn. y Profes. GP1 |
| Wandosell Jurado | Francisco | 213 | 4561 | fwandosell(at)cbm.csic.es | E. Profesores de Investigación de Organismos Públicos de Investigación |
Relevant publications:
- R-Ras1 and R-Ras2 Expression in Anatomical Regions and Cell Types of the Central Nervous System. Garcia-Martin G, Sanz-Rodriguez M, Alcover-Sanchez B, Pereira MP, Wandosell F, Cubelos B. Int J Mol Sci. 2022 Jan 17;23(2):978. doi: 10.3390/ijms23020978.
- Diets with Higher ω-6/ω-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice. Ordóñez-Gutiérrez L, Fábrias G, Casas J, Wandosell F. Int J Mol Sci. 2021 Oct 9;22(20):10907. doi: 10.3390/ijms222010907.
- Editorial: Neuroprotection in Synaptic Signalling During Neurological Disorders. Otero-Losada M, Wandosell FG, Capani F. Front Synaptic Neurosci. 2021 Sep 3;13:746487. doi: 10.3389/fnsyn.2021.746487.
- Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction. Benito-Cuesta I, Ordoñez-Gutierrez L, Wandosell F. Metabolites. 2021 Jun 26;11(7):421. doi: 10.3390/metabo11070421.
- WIP, YAP/TAZ and Actin Connections Orchestrate Development and Transformation in the Central Nervous System. Antón IM, Wandosell F. Front Cell Dev Biol. 2021 Jun 14;9:673986. doi: 10.3389/fcell.2021.673986.
- Pathways involved in remyelination after cerebral ischemia. Garcia-Martin G, Alcover-Sanchez B, Wandosell F, Cubelos B. Curr Neuropharmacol. 2021 Jun 9. doi: 10.2174/1570159X19666210610093658.
- Absence of R-Ras1 and R-Ras2 causes mitochondrial alterations that trigger axonal degeneration in a hypomyelinating disease model. 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. Glia. 2021 Mar;69(3):619-637. doi: 10.1002/glia.23917.
- AMPK activation does not enhance autophagy in neurons in contrast to MTORC1 inhibition: different impact on β-amyloid clearance. Benito-Cuesta I, Ordóñez-Gutiérrez L, Wandosell F. Autophagy. 2021 Mar;17(3):656-671. doi: 10.1080/15548627.2020.1728095.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S…. Autophagy. 2021 Jan;17(1):1-382. doi: 10.1080/15548627.2020.1797280.
- WIP Modulates Oxidative Stress through NRF2/KEAP1 in Glioblastoma Cells. Escoll M, Lastra D, Robledinos-Antón N, Wandosell F, Antón IM, Cuadrado A. Antioxidants (Basel). 2020 Aug 20;9(9):773. doi: 10.3390/antiox9090773.
- R-Ras GTPases Signaling Role in Myelin Neurodegenerative Diseases. Alcover-Sanchez B, Garcia-Martin G, Wandosell F, Cubelos B. Int J Mol Sci. 2020 Aug 17;21(16):5911. doi: 10.3390/ijms21165911.
- Nanoliposomes as a Therapeutic Tool for Alzheimer's Disease. Ordóñez-Gutiérrez L, Wandosell F. Front Synaptic Neurosci. 2020 May 25;12:20. doi: 10.3389/fnsyn.2020.00020.
- Crosstalk between WIP and Rho family GTPases. Antón IM, Gómez-Oro C, Rivas S, Wandosell F. Small GTPases. 2020 May;11(3):160-166. doi: 10.1080/21541248.2017.1390522.
- Ovarian Hormone-Dependent Effects of Dietary Lipids on APP/PS1 Mouse Brain. Herrera JL, Ordoñez-Gutierrez L, Fabrias G, Casas J, Morales A, Hernandez G, Acosta NG, Rodriguez C, Prieto-Valiente L, Garcia-Segura LM, Wandosell FG, Alonso R. Front Aging Neurosci. 2019 Dec 19;11:346. doi: 10.3389/fnagi.2019.00346.
- Editorial: Neuroprotection in Brain Hypoxia. Otero-Losada M, Wandosell FG, Garcia-Segura LM, Capani F. Front Neurosci. 2019 Mar 22;13:212. doi: 10.3389/fnins.2019.00212.
- Botulinum Neurotoxin Light Chains Expressed by Defective Herpes Simplex Virus Type-1 Vectors Cleave SNARE Proteins and Inhibit CGRP Release in Rat Sensory Neurons. Joussain C, Le Coz O, Pichugin A, Marconi P, Lim F, Sicurella M, Salonia A, Montorsi F, Wandosell F, Foster K, Giuliano F, Epstein AL, Aranda Muñoz A. Toxins (Basel). 2019 Feb 19;11(2):123. doi: 10.3390/toxins11020123.
- Energy-Sensing Pathways in Ischemia: The Counterbalance Between AMPK and mTORC. Cespedes A, Villa M, Benito-Cuesta I, Perez-Alvarez MJ, Ordoñez L, Wandosell F. Curr Pharm Des. 2019;25(45):4763-4770. doi: 10.2174/1381612825666191210152156.
- WIP-YAP/TAZ as A New Pro-Oncogenic Pathway in Glioma. Rivas S, Antón IM, Wandosell F. Cancers (Basel). 2018 Jun 9;10(6):191. doi: 10.3390/cancers10060191.
- R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System. Sanz-Rodriguez M, Gruart A, Escudero-Ramirez J, de Castro F, Delgado-García JM, Wandosell F, Cubelos B. J Neurosci. 2018 May 30;38(22):5096-5110. doi: 10.1523/JNEUROSCI.3364-17.2018.
- Sex steroid hormones as neuroprotective elements in ischemia models. Céspedes Rubio ÁE, Pérez-Alvarez MJ, Lapuente Chala C, Wandosell F. J Endocrinol. 2018 May;237(2):R65-R81. doi: 10.1530/JOE-18-0129.
- Ovarian Function Modulates the Effects of Long-Chain Polyunsaturated Fatty Acids on the Mouse Cerebral Cortex. Herrera JL, Ordoñez-Gutierrez L, Fabrias G, Casas J, Morales A, Hernandez G, Acosta NG, Rodriguez C, Prieto-Valiente L, Garcia-Segura LM, Alonso R, Wandosell FG. Front Cell Neurosci. 2018 Apr 24;12:103. doi: 10.3389/fncel.2018.00103.
- Role of Akt Isoforms Controlling Cancer Stem Cell Survival, Phenotype and Self-Renewal. Rivas S, Gómez-Oro C, Antón IM, Wandosell F. Biomedicines. 2018 Mar 7;6(1):29. doi: 10.3390/biomedicines6010029.
- Role of mTORC1 Controlling Proteostasis after Brain Ischemia. Perez-Alvarez MJ, Villa Gonzalez M, Benito-Cuesta I, Wandosell FG. Front Neurosci. 2018 Feb 15;12:60. doi: 10.3389/fnins.2018.00060.
- Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-β Levels in Primary Neurons from an Alzheimer's Disease Transgenic Model. Ordóñez-Gutiérrez L, Benito-Cuesta I, Abad JL, Casas J, Fábrias G, Wandosell F. Pharm Res. 2018 Feb 6;35(3):49. doi: 10.1007/s11095-017-2312-2.
- Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer's disease-like transgenic mouse model. Carradori D, Balducci C, Re F, Brambilla D, Le Droumaguet B, Flores O, Gaudin A, Mura S, Forloni G, Ordoñez-Gutierrez L, Wandosell F, Masserini M, Couvreur P, Nicolas J, Andrieux K. Nanomedicine. 2018 Feb;14(2):609-618. doi: 10.1016/j.nano.2017.12.006.
- Ordóñez-Gutiérrez L, Posado-Fernández A, Ahmadvand D, Lettiero B, Wu L, Antón M, Flores O, Moghimi SM, Wandosell F. (2017). “ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer’s disease is restricted to aged animals” Biomaterials.112:141-152 , doi: 10.1016/j.biomaterials.2016.07.027
- Escoll M, Gargini RA, IM Anton*, Wandosell F*. (2017). “Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ”. Oncogene;36(25):3515-3527. doi: 10.1038/onc.2016.518.
- Irene Benito-Cuesta, Héctor Diez, Lara Ordoñez and Francisco Wandosell (2017)” Assessment of autophagy in neurons and in brain tissue.” Cells, 6: 3; doi: 10.3390/cells6030025
- Inés Anton, Carla Gomez-Oro, Sergio Rivas and Francisco Wandosell (2018). “Crosstalk between WIP and Rho family GTPases" : Small GTPases 1-7(Epub 2018 Jan 29) doi: 10.1080/21541248.2017.1390522
- Lara Ordóñez-Gutiérrez, Irene Benito-Cuesta, José Luis Abad, Josefina Casas, Gemma Fabrias and Francisco Wandosell .(2018). "Dihydroceramide desaturase 1 inhibitors reduce amyloid-β levels in primary neurons from an Alzheimer's disease transgenic model" Pharmaceutical Research 35:3-49 doi 10.1007/s11095-017-2312-2
- Dario Carradori, Claudia Balducci, Davide Brambilla, Francesca Re, Benjamin Le Droumaguet, Fabio De Nicolo, Tatiana Rozzi, Orfeu Flores, Alice Gaudin, SimonaMura, Valérie Nicolas, Gianluigi Forloni, Lara Ordoñez-Gutierrez, Francisco Wandosell, Massimo Masserini, Julien Nicolas, Patrick Couvreur, and Karine Andrieux. (2018). “Antibody-Functionalized Polymer Nanoparticle Leading to Memory Recovery in Alzheimer's Disease-like Transgenic Mouse Model” Nanomedicine:Nanotechnology, Biology, and Medicine 14:2-609-618. doi: 10.1016/j.nano.2017.12.006.
- Ángel Enrique Céspedes Rubio*, Maria José Pérez-Alvarez*, Catalina Lapuente Chala and Francisco Wandosell. (2018). “ Sex steroid hormones as neuroprotective elements in ischemia models” J. Endocrinol.;237(2):R65-R81. doi: 10.1530/JOE-18-0129.
- Perez-Alvarez, M. J.; Villa Gonzalez, M.; Benito-Cuesta, I. and Wandosell, F. G (2018) Role of mTORC1 Controlling Proteostasis after Brain Ischemia. Front Neurosci. 12: 60; doi : 10.3389/fnins.2018.00060
- Rivas, S., Gomez-Oro, C., Anton, I. M. and Wandosell, F. (2108) “Role of Akt Isoforms Controlling Cancer Stem Cell Survival, Phenotype and Self-Renewal” Biomedicines 6: 1; doi: 10.3390/biomedicines6010029
- Jose L. Herrera, Lara Ordoñez-Gutierrez , Gemma Fabrias , Josefina Casas , Araceli Morales , Guadalberto Hernandez , Nieves G. Acosta5, Covadonga Rodriguez , Luis Prieto-Valiente, Luis M. Garcia-Segura*, Rafael Alonso* and Francisco G. Wandosell * (2018). "Ovarian function modulates the effects of long-chain polyunsaturated fatty acids on the mouse cerebral cortex", Frontiers in Neuroscience; 12:103. doi: 10.3389/fncel.2018.00103. eCollection
- Sergio Rivas, Inés M. Antón, and Francisco Wandosell (2018) “WIP‐YAP/TAZ as a new pro‐oncogenic pathway in glioma”. Cancers 10:6 , doi: 10.3390/cancers10060191
- Miriam Sanz-Rodriguez, Juan Escudero-Ramirez, Fernando de Castro, Agnès Gruart, José María Delgado-García, Francisco Wandosell and Beatriz Cubelos*. (2018) "R-Ras1 and R-Ras2 are essential for oligodendrocyte differentiation and survival for correct myelination in the central nervous system," The Journal of Neuroscience (2018) 38(22):5096 –5110. doi: 10.1523/JNEUROSCI.3364-17.2018
- Sergio Rivas, Inés M. Antón, and Francisco Wandosell (2018) WIP‐YAP/TAZ as a new pro‐oncogenic pathway in glioma. Cancers 2018, 10(6), 191;doi.org/10.3390/cancers10060191
Doctoral theses:
- Irene Benito Cuesta, “Análisis de las vías de inducción de Autofagia en neuronas y su papel neuroprotector en un modelo transgénico de la enfermedad de Alzheimer“, Sobresaliente Cum Laude, Universidad Autónoma de Madrid, Facultad de Ciencias, 26/07/2017, Director: Dr. Francisco Wandosell.
- Sergio Rivas Muñoz "Análisis de la vía protumoral WP-YAP/TAZ mediante proteómica y transcriptómica diferencial". Sobresaliente cum laude, Universidad Autónoma de Madrid 2021. Directores: Francisco Wandosell e Inés Antón
Ongoing projects:
- Programme I+D+i-RETOS- RTI2018-096303-B-C1. “Papel de la vía AKT/YAP/TAZ en Patologías del Sistema Nervioso Central”. (2019-2021) IP1- Francisco Wandosell; IP2- Inés M. Antón Gutiérrez
- ISCIII-CIBERNED –Proyectos Colaborativos- PI2016/01”- (2017-2018)- Coordinador .Dr. I.Torres-Aleman
- Fundación RAMON ARECES -Proyectos de investigación en Ciencias de la Vida y de la Materia, correspondientes al XVIII Concurso Nacional. (2018-20). IP. Drª. Ines M. Anton ; coIP Francisco Wandosell (CIBERNED)
- CAM-Biomedicina 2017, B2017/BMD-3700; “BASES METABÓLICAS DE LA NEURODEGENERACIÓN” (NEUROMETAB-CM)-Coordinador: Dr. Gonzalez Castaño, Jose (UAM);IP .Dr. F. Wandosell (CBM-CSIC)
- RETOS-COLABORACION 2017-2019 (RTC2017-5994-1). “Fármacos Innovadores para el tratamiento de la Enfermedad de Alzheimer: Estudios preclínicos de la eficacia y toxicidad bajo condiciones BLP por vía oral” Coordinador: ALLINKY BIOPHARMA SL; IP- CBM-CSIC: F Wandosell.
EU projects:
- COST-EU Framework Prog. H2020- “European Network of Multidisciplinary Research and Translation of Autophagy knowledge” TRANSAUTOPHAGY COST ACTION CA15138, (ref. OC-2015-1-19840).
- ERA-NET NEURON 2016 (PCIN-2016-108) “Regulacion del reflejo de micción después de lesiónmédular: abolición por silenciamiento de losaferentes de las fibras C de la vejiga hiper-excitados mediante terapia génica para restaurar la continencia y la micción”-ELPIS". Coordinator: Pr. François Giuliano (Francia); PI-(CBM-CSIC): F Wandosell (Spain)
Teaching activities:
- Máster en Biomedicina Molecular. Departamento de Biología Molecular y de Bioquímica (UAM). Módulo: ENFERMEDADES NEUROLÓGICAS (BMM6) (2014-2019) Coordinadores: Dr. Javier Díaz Nido (Dpto. Biología Molecular UAM), Dr. Francisco Wandosell (CBMSO, CSIC-UAM).
Others:
- Our group belong to Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED): PI - F Wandosell
