Macarena Arrázola
Assistant Professor
Chemist and PhD in Biological Sciences, Cell and Molecular Biology from the Pontifical Catholic University of Chile (2014). During his doctorate he determined the mechanism that regulates the opening of the mitochondrial permeability transition pore and how its inhibition prevents amyloid beta oligomers-induced neurodegeneration. She did her first postdoctoral trainning at the Centre de la Biologie Intégrative (CBI) at the University Paul Sabatier Toulouse III, France. During her stay she studied the function of the mitochondrial protein OPA1 in neuronal physiology and pathology. Using in vitro neuronal cultures and a murine model of Dominant Optical Atrophy (DOA) by haploinsufficiency of the OPA1 gene, she determined that the absence of OPA1 affects neuronal maturation and promotes death of retinal neurons and degeneration of their axons, affecting the visual function. In 2017 she returned to Chile to pursue his second postdoctoral degree at the CIB. The main finding was to determine that necroptosis, a programmed necrotic cell death pathway, regulates axonal degeneration induced by damage. This work was the basis for demonstrating that both neurodegeneration, synaptic dysfunction and cognitive impairment associated with aging are regulated by the progressive activation of necroptosis in the hippocampus, proposing therapeutic strategies, with a geroprotective perspective based on genetic and pharmacological inhibition of necroptosis effectors. In 2022 she joined the CIB as a principal investigator. Her research line is focused on determining the mechanisms involved in optic nerve degeneration in neurodegenerative mitochondrial diseases such as DOA, and aging-associated optical neuropathies such as glaucoma. At the molecular level, her studies are directed to understand the necroptosis-mitochondria axis and its impact on mitochondrial dynamics and mitophagy processes. Her team uses diverse techniques, such as ex vivo retinal cultures to study isolated axons, retinal and optic nerve histology, imaging to evaluate mitochondrial and neuronal morphology, experimental models of glaucoma and pharmacological and genetic interventions through intravitreal injections.
PUBLICATIONS
Hernández J, Panadero-Medianero C, Arrázola MS, Ahumada M. (2024) Mimicking the Physicochemical Properties of the Cornea: A Low-Cost Approximation Using Highly Available Biopolymers. Polymers (Basel) 16(8):1118. doi: 10.3390/polym16081118.
Atamena D, Gurram V, Petsophonsakul P, Khosrobakhsh F, Arrázola MS, Botella M, Wissinger B, Szelechowski M, Belenguer P. (2023) Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis. Front. Mol. Neurosci 16:1241222. doi: 10.3389/fnmol.2023.1241222.
Santos N, Valenzuela S, Segura C, Osorio-Roman I, Arrázola MS, Panadero-Medianero C, Santana PA, Ahumada M. (2023) Poly(ethylene imine)-chitosan carbon dots: study of its physical-chemical properties and biological in vitro performance. Discov Nano 18(1):129.
Andraini T, Moulédous L, Petsophonsakul P, Florian C, Gauzin S, Botella M, Arrázola MS, Nikolla K, Philip A, Leydier A, Marque M, Pelloquin-Arnauné L, Belenguer P, Rampon C, Miquel MC (2023) Mitochondrial OPA1 deficiency is associated to reversible defects in spatial memory related to adult neurogenesis in mice. eNeuro, 10 (11) ENEURO.0073-23.2023. doi: 10.1523/ENEURO.0073-23.2023.
Arrázola MS, Lira M, Veliz-Valverde F, Quiroz G, Iqbal S, Eaton SL, Lamont DJ, Huerta H, Ureta G, Bernales S, Cárdenas CJ, Cerpa W, Wishart TM and Court FA. (2023) Necroptosis inhibition counteracts neurodegeneration, memory decline, and key hallmarks of aging, promoting brain rejuvenation. Aging Cell, May;22(5):e13814. doi: 10.1111/acel.13814.
Our study reveals that necroptosis contributes to the age-associated neurodegeneration, affecting hippocampal neuronal connectivity and cognitive functions, such as, learning and memory performance of aged mice. Therefore, necroptosis inhibition constitutes a potential strategy for the development of therapeutic tools to treat age-related brain disabilities and to promote brain rejuvenation.
Arrázola MS and Court FA. (2023) Commentary on "PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons". Neural Regen Res. 18(2):341. doi: 10.4103/1673-5374.346543.
Ramos-Fernández E, Arrázola MS*, Oliva CA, Arredondo S, Varela-Nallar L and Inestrosa NC. (2021) Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2a HRI kinase. Sci Rep. 11:7395. doi: 10.1038/s41598-021-86708-y.
Montecinos-Oliva C, Arrázola MS, Jara C, Tapia-Rojas C, Inestrosa NC. (2020) Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation. Pharmaceuticals 13(2):24. doi: 10.3390/ph13020024.
Arrázola MS and Court FA. (2019) Compartmentalized necroptosis activation in excitotoxicity-induced axonal degeneration: a novel mechanism implicated in neurodegenerative disease pathology. Neural Regen Res. 14(8):1385-1386. doi: 10.4103/1673-5374.253520.
Chao de la Barca JM, Arrázola MS, Bocca C, Arnauné-Pelloquin L, Iuliano O, Tcherkez G, Lenaers G, Simard G, Belenguer P, Reynier P. (2019) The Metabolomic Signature of Opa1 Deficiency in Rat Primary Cortical Neurons Shows Aspartate/Glutamate Depletion and Phospholipids Remodeling. Sci Rep. 9(1):6107. doi: 10.1038/s41598-019-42554-7.
Arrázola MS, Saquel C, Catalán RJ, Barrientos SA, Hernandez DE, Catenaccio A, Court FA. (2019) Axonal degeneration is mediated by necroptosis activation. J Neurosci. Mar 13. pii: 0881-18. doi: 10.1523/JNEUROSCI.0881-18.2019.
This work represents a critical advance for the field of axonal pathology since it identifies a defined degenerative pathway involved in axonal degeneration in both the peripheral nervous system and the CNS, a process that has been proposed as an early event in several neurodegenerative conditions and a major contributor to neuronal death. The identification of necroptosis as a key mechanism for axonal degeneration is an important step toward the development of novel therapeutic strategies for nervous-system disorders, particularly those related to chemotherapy-induced peripheral neuropathies or CNS diseases in which axonal degeneration is a common factor.
Arrázola MS, Andraini T, Szelechowski M, Mouledous L, Arnauné-Pelloquin L, Davezac N, Belenguer P, Rampon C, Miquel MC. (2019) Mitochondria in Developmental and Adult Neurogenesis. Neurotox Res. doi: 10.1007/s12640-018-9942-y.
Richetin K, Moulis M, Millet A, Arrázola MS, Andraini T, Hua J, Davezac N, Roybon L, Belenguer P, Miquel MC, Rampon C. (2017) Amplifying mitochondrial function rescues adult neurogenesis in a mouse model of Alzheimer’s disease. Neurobiol Dis. 102:113-124. doi: 10.1016/j.nbd.2017.03.002.
Arrázola MS, Ramos-Fernández E, Cisternas P, Ordenes D, Inestrosa NC (2017) Wnt signaling prevents the Ab oligomer-induced mitochondrial permeability transition pore opening preserving mitochondrial structure in hippocampal neurons. PLoS One 12(1): e0168840. doi: 10.1371/journal.pone.0168840.
Tapia-Rojas C, Lindsay CB, Montecinos-Oliva C, Arrázola MS, Retamales RM, Bunout D, Hirsch S, Inestrosa NC. (2015) Is L-methionine a trigger factor for Alzheimer's-like neurodegeneration?: Changes in Aβ oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice. Mol Neurodegener. 10 :62. doi: 10.1186/s13024-015-0057-0.
Arrázola MS, Silva-Alvarez C, Inestrosa NC. (2015) How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario. Front Cell Neurosci. 9:166. doi: 10.3389/fncel.2015.00166.
Minniti AN, Arrázola MS, Bravo-Zehnder M, Ramos F, Inestrosa NC, Aldunate R. (2015) The Protein Oxidation Repair Enzyme Methionine Sulfoxide Reductase A Modulates Aβ Aggregation and Toxicity In Vivo. Antioxid Redox Signal. 22(1):48-62. doi: 10.1089/ars.2013.5803
RESEARCH LINES
Mecanismos de degeneración del sistema nervioso central y su impacto en el deterioro cognitivo asociado al envejecimiento.
Degeneración del nervio óptico y retina durante el envejecimiento, y en neuropatías ópticas
Estrategias neuroprotectoras para el tratamiento de glaucoma y su progresión con la edad
PROJECTS
Activo
2022-2024. From proof of principle to novel therapeutic targets in Dominant Optic Atrophy: The role of necroptosis/Pgam5 signaling in optic nerve degeneration. FONDECYT Iniciación 11220120 (Investigador Principal)
2023-2024. Accelerating biological understanding and therapeutic translation for Parkinson’s disease Program - The Michael J. Fox Foundation for Parkinson’s Research. Title: Targeting RIPK3 to inhibit axonal degeneration and brain inflammation in Parkinson’s disease. (Colaborador)
Terminado
2018-2021. Contribution of chronic inflammation in neurodegeneration along aging: Role of necroptosis in the vulnerability of different neuronal populations. Fondecyt Postdoctodo, ANID.
TEAM
María Concepción Panadero, Estudiante de Doctorado en Neurobiología, Universidad Mayor
Alexandra Iribarren, Asistente de investigación, Tecnóloga Médico, Universidad Mayor
Clara Arellano, Tesista pregrado Tecnología Médica, Universidad Mayor
Vania Alegría, Tesista pregrado Tecnología Médica, Universidad Mayor
Former Lab
Javiera Paz Oporto, Tesista Pregrado Tecnología Médica, Universidad Mayor
Iván Avendaño, Tesista Pregrado Tecnología Médica, Universidad Mayor
Sofía Jiménez Le-Fort, Tesista Pregrado Tecnología Médica, Universidad Mayor
NETWORK
Nacional
Cristhian Urzúa, Laboratorio de Enfermedades Autoinmunes Oculares y Sistémicas, Universidad de Chile, Santiago.
Loreto Cuitiño, Hospital Clinico Universidad de Chile, Universidad de Chile, Santiago.
Waldo Cerpa, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago.
Felipe Court, Centro de Biología Integrativa, Universidad Mayor, Santiago.
René Vidal, Centro de Biología Integrativa, Universidad Mayor, Santiago.
Manuel Ahumada, Centro de Nanotecnología Aplicada, Universidad Mayor, Santiago.
Internacional
Yang Hu, Department of Ophthalmology, Stanford University, USA
Pascale Belenguer, Centre de la Biologie Intégrative (CBI), Université Paul Sabatier Toulouse III, Toulouse, France
Marion Szelechowski, INSERM UMR1291 Institut Toulousain des Maladies Infectieuses et Inflammatoires, Toulouse, France.
Cecile Delettre, Neuroscience Institute of Montpellier, France.