Grupos y Lneas de Investigacin

Degeneration and regeneration of the central nervous system

Dras. Mar Pérez, Vega García-Escudero y Mª Teresa Moreno Flores

The understanding of mechanisms involved in neurodegeneration is key for the successful of regenerative therapies. Our research encompasses the study of several fundamental aspects neurodegeneration. Alzheimer disease is a neurodegenerative disorder characterized by the accumulation of Tau protein into intracellular neurofibrillary tangles and amyloid-β peptide forming extracellular amyloid plaques. Much part of our work has been focused in the study of Tau pathology and its relevance for Alzheimer disease and other neurodegenerative pathologies. One of our principal aims is to unravel the function of the different domains of Tau protein as well as its splicing variants and transcriptional modifications.

On the other hand, cell stress is the cornerstone of all neuropathies and mitochondria is one of the main players involved this process because is the fundamental energy producer organelle as well as the principal origin of the oxidative stress. Autophagy is the cellular process by which molecules and organelles are recycled through lysosomal degradation, therefore this process is fundamental in many neurodegenerative diseases were proteinopathy is a common nexus. We have demonstrated that mitochondrial recycling by autophagy, named mitophagy, is altered in Alzheimer disease causing the abnormal accumulation of dysfunctional mitochondria together with the deleterious effects over the cells such as oxidative stress and energy deprivation. We have also studied the effect of Tau over mitophagy process.

One important part of the research in neurodegenerative diseases is the generation of human models as fundamental tools for the study of mechanisms involved in the pathology. Several unmodified patient derived cell models have demonstrated to retain the hallmarks exhibited in disease brain. We have used peripheral cell models such as fibroblasts that have revealed to exhibit similar mitophagy failure than Alzheimer disease patients’ brain. Moreover, we have explored the use of olfactory mucosa as a direct source for neural cells finding that they retain features found in Amyotrophic lateral sclerosis brains such as the toxicity over motor neurons and the inflammatory response. Furthermore, new techniques of cell reprogramming had offer us the possibility of generating living neurons from other cell sources like fibroblasts or glial cells allowing the study of degenerative diseases in a cell type relevant for the brain pathology. We use neurons derived from induced pluripotent stem cells to perform functional assays for the study mitophagy alteration in familial Alzheimer disease associated to PSEN1 mutations.

Central nervous system injury remains as non-resolved problem for modern medicine. To unravel which are the mechanisms that inhibit the regrowth of lesioned axons in order to find therapeutic solutions is one of the main objectives of our group. Cell therapy has emerged as one of the most powerful challenges for these patients. In this regard, we have focused our efforts in two different strategies. First, is the use of olfactory ensheathing glia (OEG) to drive the regrowth of axotomized neurons. Ensheathing glia is a specialized cell that has the innate ability to drive and allow the growth of the axons of the new neurons generated in the olfactory epithelium to reach and connect to the proper neurons of the olfactory bulb in the central nervous system. These cells have been demonstrated to induce regrowth of axons in vitro and to induce axonal regeneration and functional recovery in spinal cord lesioned animals. Accordingly, we are investigating the molecules and signaling pathways involved in OEG-dependent neuroregeneration, unveiling the role of several of them (f. ex. matrix metalloproteinase-2, brain-derived neurotrophic factor (BDNF); and thrombin signaling and plasminogen activator inhibitor-1). Secondly, we will explore the use of reprogramming techniques to directly transform the astrocytes of glial scar into neurons in order to bypass the lesioned area and recover the lost connections.

Pérez Martínez, Mar, Ph.D.

García-Escudero Barreras, Vega, Ph.D.

Moreno Flores, M. Teresa, Ph.D.

 

Portela Lomba, Maria (Ph.D. student)

Daniel Ruiz Gabarre (Master Student)

Santiago Reyes León (Master Student)

Joaquín García Cordero (Master Student)

REFERENCES

  • Pérez, M, Medina, M, Hernández, F and Avila, J.  "Secretion of full-length Tau or Tau fragments in cell culture models. Propagation of Tau in vivo and in vitro". Biomolecular Concepts. in press.
  • Cordero JC, García-Escudero R, Avila J, Gargini R, García-Escudero V. “Benefit of Oleuropein Aglycone for Alzheimer’s Disease by Promoting Autophagy”. Oxid Med Cell Longev. 2018, In press. Review.
  • Gómez RM, Sánchez MY, Portela-Lomba M, Ghotme K, Barreto GE, Sierra J, Moreno-Flores MT. "Cell therapy for spinal cord injury with olfactory ensheathing glia cells (OECs)". Glia 2018, Jan 13. doi: 10.1002/glia.23282. [Epub ahead of print] Review.
  • Martín-Maestro P, Gargini R, García E, Perry G, Avila J, García-Escudero V. “Slower Dynamics and Aged Mitochondria in Sporadic Alzheimer's Disease”. Oxid Med Cell Longev. 2017;2017:9302761. doi: 10.1155/2017/9302761. Epub 2017 Oct 19.
  • Martín-Maestro P, Gargini R, A Sproul A, García E, Antón LC, Noggle S, Arancio O, Avila J, García-Escudero V. “Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer's Disease-Associated Presenilin 1 Mutation”. Front Mol Neurosci. 2017 Sep 14;10:291. doi: 10.3389/fnmol.2017.00291. eCollection 2017.
  • García-Escudero V, Gargini R, Martín-Maestro P, García E, García-Escudero R, Avila J. “Tau mRNA 3'UTR-to-CDS ratio is increased in Alzheimer disease”. Neurosci Lett. 2017 Aug 10;655:101-108. doi: 10.1016/j.neulet.2017.07.007. Epub 2017 Jul 8.
  • Pérez M, Cuadros R, Hernández F, Avila J. “Secretion of full-length tau or tau fragments in a cell culture model”. Neurosci Lett. 2016 Nov 10; 634: 63-69.
  • Fu QQ, Wei L, Sierra J; Cheng JZ, Moreno-Flores MT, You H; Yu HR. “Olfactory Ensheathing Cell-Conditioned Medium Reverts Aβ25–35-Induced Oxidative Damage in SH-SY5Y Cells by Modulating the Mitochondria-Mediated Apoptotic Pathway”. Cell Mol Neurobiol. 2016 Nov 2. [Epub ahead of print].
  • Gargini R, García-Escudero V, Izquierdo M, Wandosell F. “Oncogene-mediated tumor transformation sensitizes cells to autophagy induction”. Oncol Rep. 2016 Jun; 35(6): 3689-95.
  • Martín-Maestro P, Gargini R, Perry G, Avila J, García-Escudero V. “PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer’s disease”. Hum Mol Genet. 2016 Feb 15;25(4):792-806.
  • Plaza N, Simón D, Sierra J, Moreno-Flores MT. “Transduction of an immortalized olfactory ensheathing glia cell line with the green fluorescent protein (GFP) gene: evaluation of its neuroregenerative capacity as a proof of concept”. Neurosci Lett 2016 Jan 26; 612: 25-31.
  • Reginensi D, Carulla P, Nocentini S, Seira O, Serra-Picamal X, Torres-Espín A, Matamoros-Angles A, Gavín R, Moreno-Flores MT, Wandosell F, Samitier J, Trepat X, Navarro X, Del Río JA. “Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord”. Cell Mol Life Sci. 2015 Jul; 72: 2719-37.
  • García-Escudero V, Rosales M, Muñoz JL, Scola E, Medina J, Khalique H, Garaulet G, Rodriguez A, Lim F. “Patient-derived olfactory mucosa for study of the non-neuronal contribution to amyotrophic lateral sclerosis pathology.” J Cell Mol Med. 2015 Jun; 19(6): 1284-95.
  • Fernández-Montoya J, Pérez M. “Cathepsin D in a murine model of frontotemporal dementia with Parkinsonism-linked to chromosome 17”. Alzheimers Dis. 2015; 45(1):1-14.
  • Pérez M, Cuadros R, Pallas-Bazarra N, García C, Langa E, Jurado-Arjona J, Hernández F, Avila J. “Boronate-tau mediated uptake in neurons”. J Alzheimers Dis. 2014; 40(1): 143-51
  • de Cristóbal J, García-García L, Delgado M, Pérez M, Pozo MA, Medina M. “Longitudinal assessment of a transgenic animal model of tauopathy by FDG-PET imaging”. J Alzheimers Dis. 2014; 40 Suppl 1:S79-89.
  • Leon-Espinosa G, Garcia E, García-Escudero V, Hernandez F, Defelipe J, Avila J. “Changes in tau phosphorylation in hibernating rodents”. J Neurosci Res. 2013; 91: 954-62.
  • García-Escudero V, Martin-Maestro P, Perry G, Avila J. “Deconstructing mitochondrial dysfunction in Alzheimer disease”. Oxid Med Cell Longev. 2013; 2013: 162152.
  • Moreno-Flores MT, Ferón F, Arvanian V, Blesch A, Curt A, Fink DJ , Mata M , Nakashima K, Navarro X, Rodríguez FJ, Schwartz M, Svensson M, Sundstrom E, Romero J, Lim F. “The 2nd Step by Step International Spinal Cord Repair Meeting—Combining research Step by Step into multi-pronged approaches for spinal cord repair”. J. Biomed Sci Eng 2013; 6: 21-32.
  • Avila J, Leon-Espinosa G, Garcia E, García-Escudero V, Hernandez F, Defelipe J. “Tau Phosphorylation by GSK3 in Different Conditions. Int J Alzheimers Dis. 2012; 2012: 578373.
  • Garcia-Escudero V, Garcia-Gomez A, Langa E, Martin-Bermejo MJ, Ramirez-Camacho R, Garcia-Berrocal JR, Moreno-Flores MT, Avila J, Lim F. “Patient-derived olfactory mucosa cells but not lung or skin fibroblasts mediate axonal regeneration of retinal ganglion neurons”. Neurosci Lett. 2012; 509: 27-32.
  • Nocentini S, Reginensi D, Garcia S, Carulla P, Moreno-Flores MT, Wandosell F, Trepat X, Bribian A, Del Río JA. “Myelin-associated proteins block the migration of olfactory ensheathing cells: an in vitro study using single cell tracking and traction force microscopy”. Cell Mol Life Sci. 2012 May; 69: 1689-703.
  • Simón D, Martín-Bermejo MJ, Gallego-Hernández MT, Pastrana E, García-Escudero V, García-Gómez A, Lim F, Díaz-Nido J, Ávila J, Moreno-Flores MT. “Expression of plasminogen activator inhibitor-1 by olfactory ensheathing glia promotes axonal regeneration”. Glia. 2011; 59(10):1458-71.
  • Gargini R*, García-Escudero V*, Izquierdo M.Therapy mediated by mitophagy abrogates tumor progression”. Autophagy. 2011; 7(5):466-76 *contribución equivalente.
  • García-Escudero V, Gargini R, Gallego-Hernández MT, García-Gómez A, Martín-Bermejo MJ, Simón D, Delicado A, Moreno-Flores MT, Ávila J, Lim F. A neuroregenerative human ensheathing glia cell line with conditional rapid growth. Cell Transplant. 2011; 20(2):153-66.
  • Velásquez ZD, Pérez M, Morán MA, Yanez AJ, Avila J, Slebe JC, Gómez-Ramos P. “Ultrastructural localization of fructose-1,6-bisphosphatase in mouse brain” Microsc Res Tech. 2011 Apr;74(4):329-36
  • Sirerol-Piquer M, Gomez-Ramos P, Hernández F, Perez M, Morán MA, Fuster-Matanzo A, Lucas JJ, Avila J, García-Verdugo JM. “GSK3β overexpression induces neuronal death and a depletion of the neurogenic niches in the dentate gyrus”. Hippocampus. 2011 Aug; 21(8):910-22.
  • García-Escudero V, García-Gómez A, Gargini R, Martín-Bermejo MJ, Langa E, García de Yébenes J, Delicado A, Ávila J, Moreno-Flores MT, Lim F. “Prevention of Senescence Progression in Reversibly Immortalized Human Ensheathing Glia Permits their Survival after Deimmortalization” Mol Ther. 2010; 18(2):394-403.
  • Lim F*, Martín-Bermejo MJ*, García-Escudero V, Gallego-Hernández MT, García-Gómez A, Rábano A, Díaz-Nido J, Ávila J, Moreno-Flores MT. “Reversibly immortalized human olfactory ensheathing glia from an elderly donor maintain neuroregenerative capacity” Glia. 2010; 58(5):546-58. *contribución equivalente.
  • Gómez de Barreda E, Pérez M, Gómez-Ramos P, de Cristóbal J, Martín-Maestro P, Morán M A,  Dawson H N, Vitek M P, Lucas J J,  Hernández F, Avila JTau-knock-out mice mice show reduced GSK3 induced hippocampal degeneration and learning déficits.  Neurobiol Dis. 37: 622-29 (2010)
  • Avila J, Gómez de Barreda E, Engel T, Pérez M, Martín-Maestro P, Fuster-Matanzo A, Goñi-Oliver P, Lucas JJ, Hernández F. “Tau kinase I overexpression induces dentate gyrus degeneration”. Neurodegener Dis. 2010; 7(1-3):13-5.

El Trabajo de Fin de Grado de Nutrición Humana y Dietética realizado por Joaquín García Cordero bajo la supervisión de Vega García-Escudero, titulado “Aceite de Oliva Virgen, Autofagia y Alzheimer: Efectos de la Oleuropeína Aglicona” no sólo obtuvo la máxima calificación de Matrícula de Honor en el curso 2016-2017, si no que fue galardonado con el premio Dietista-Nutricionista Promesa de 2017 en la VI Jornada ADDINMA - Asociación Dietistas Nutricionistas de Madrid. Además, ese mismo trabajo ha sido aceptado para su publicación en la revista “Oxidative Medicine and Cellular Longevity” en el número especial “Polyphenols Targeting Brain Cells Longevity, Brain's Redox Status, and Neurodegenerative Diseases (FTBC)”.