Browsing by Author "Zanlungo Matsuhiro, Silvana"

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    c-Abl activates RIPK3 signaling in Gaucher disease
    (2021) Yañez Henríquez, María José; Campos, F.; Marín Marín, Tamara Alejandra; Klein Posternack, Andrés David; Futerman, A. H.; Álvarez, Alejandra R.; Zanlungo Matsuhiro, Silvana
    Gaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal β-glucosidase (GBA) enzyme. GD affects several organs and tissues, including the brain in certain variants of the disease. Heterozygous GBA1 variants are a major genetic risk factor for developing Parkinson's disease. The RIPK3 kinase is relevant in GD and its deficiency improves the neurological and visceral symptoms in a murine GD model. RIPK3 mediates necroptotic-like cell death: it is unknown whether the role of RIPK3 in GD is the direct induction of necroptosis or if it has a more indirect function by mediating necrosis-independent. Also, the mechanisms that activate RIPK3 in GD are currently unknown. In this study, we show that c-Abl tyrosine kinase participates upstream of RIPK3 in GD. We found that the active, phosphorylated form of c-Abl is increased in several GD models, including patient's fibroblasts and GBA null mice. Furthermore, its pharmacological inhibition with the FDA-approved drug Imatinib decreased RIPK3 signaling. We found that c-Abl interacts with RIPK3, that RIPK3 is phosphorylated at a tyrosine site, and that this phosphorylation is reduced when c-Abl is inhibited. Genetic ablation of c-Abl in neuronal GD and GD mice models significantly reduced RIPK3 activation and MLKL downstream signaling. These results showed that c-Abl signaling is a new upstream pathway that activates RIPK3 and that its inhibition is an attractive therapeutic approach for the treatment of GD.
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    c-Abl kinase at the crossroads of healthy synaptic remodeling and synaptic dysfunction in neurodegenerative diseases
    (2023) Gutiérrez García, Daniela A.; Chandía Cristi, América Valeska; Yanez, Maria Jose; Zanlungo Matsuhiro, Silvana; Álvarez Rojas, Alejandra
    Our ability to learn and remember depends on the active formation, remodeling, and elimination of synapses. Thus, the development and growth of synapses as well as their weakening and elimination are essential for neuronal rewiring. The structural reorganization of synaptic complexes, changes in actin cytoskeleton and organelle dynamics, as well as modulation of gene expression, determine synaptic plasticity. It has been proposed that dysregulation of these key synaptic homeostatic processes underlies the synaptic dysfunction observed in many neurodegenerative diseases. Much is known about downstream signaling of activated N-methyl-D-aspartate and a-amino-3-hydroxy5-methyl-4-isoazolepropionate receptors; however, other signaling pathways can also contribute to synaptic plasticity and long-lasting changes in learning and memory. The non-receptor tyrosine kinase c-Abl (ABL1) is a key signal transducer of intra and extracellular signals, and it shuttles between the cytoplasm and the nucleus. This review focuses on c-Abl and its synaptic and neuronal functions. Here, we discuss the evidence showing that the activation of c-Abl can be detrimental to neurons, promoting the development of neurodegenerative diseases. Nevertheless, c-Abl activity seems to be in a pivotal balance between healthy synaptic plasticity, regulating dendritic spines remodeling and gene expression after cognitive training, and synaptic dysfunction and loss in neurodegenerative diseases. Thus, c-Abl genetic ablation not only improves learning and memory and modulates the brain genetic program of trained mice, but its absence provides dendritic spines resiliency against damage. Therefore, the present review has been designed to elucidate the common links between c-Abl regulation of structural changes that involve the actin cytoskeleton and organelles dynamics, and the transcriptional program activated during synaptic plasticity. By summarizing the recent discoveries on c-Abl functions, we aim to provide an overview of how its inhibition could be a potentially fruitful treatment to improve degenerative outcomes and delay memory loss.
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    c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration
    (De Gruyter, 2023) Martinez Saavedra, Alexis; Lamaizon Muñoz, Cristián Nicolás; Valls Jimenez, Cristián; Llambi, Fabien; Leal Reyes, Nancy Valeria; Fitzgerald, Patrick; Guy, Cliff; Kaminsk,i Marcin M.; Inestrosa Cantin, Nibaldo; van Zundert, Brigitte; Cancino, Gonzalo; Dulcey, Andrés E.; Zanlungo Matsuhiro, Silvana; Marugan, Juan J.; Hetz, Claudio; Green, Douglas R.; Alvarez Rojas, Alejandra
    The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.
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    Deficiency of Niemann-Pick C1 protein protects against diet-induced gallstone formation in mice
    (2010) Morales France, María Gabriela; Amigo Böker, Ludwig Peter; Balboa Castillo, Elisa Ivana; Acuña Aravena, Mariana Loreto; Castro, Juan; Molina, Héctor; Miquel P., Juan Francisco; Nervi, Flavio; Rigotti Rivera, Attilio; Zanlungo Matsuhiro, Silvana
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    MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content.
    (2017) Balboa Castillo, Elisa Ivana; Castro, J.; Cancino, G. I.; Matias, N.; Saez P., Jose; Martinez, A.; Álvarez Rojas, Alejandra; Garcia Ruiz, C.; Fernandez Checa, J. C.; Zanlungo Matsuhiro, Silvana; Pinochet, M.
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    Modulación del procesamiento de la proteína precursora del amiloide por la tirosina quinasa C-ABL y su implicancia en la enfermedad de Niemann-Pick tipo C /
    (2016) Yáñez Henríquez, María José; Álvarez Rojas, Alejandra; Zanlungo Matsuhiro, Silvana; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    La enfermedad de Niemann-Pick tipo C (NPC) es un desorden hereditario autosómico recesivo causado por mutaciones en dos genes que codifican para las proteínas NPC1 y NPC2. Estas proteínas participan en el tráfico intracelular de lípidos y su deficiencia causa la acumulación de colesterol en los lisosomas. Sorpresivamente en distintas regiones del SNC de pacientes NPC, se han detectado aumentos del péptido β-amiloide (Aβ), el elemento patogénico causante de la pérdida sináptica y la muerte neuronal en la Enfermedad de Alzheimer (EA). Estudios in vitro e in vivo indican de que la pérdida de NPC1 conduce a un aumento significativo en los niveles de βCTF y sAPPβ. Resultados de nuestro laboratorio indican que la quinasa c-Abl se encuentra activada en la enfermedad de NPC. Además, c-Abl interactúa y fosforila la proteína precursora amiloide (APP), sin embargo, la relevancia de esta interacción no se ha definido aun. En este trabajo, se observó que la inhibición de c-Abl, mediante el uso de Imatinib un inhibidor específico de c-Abl o expresando un ARN interferente (shRNA) específico para c-Abl, reduce los niveles de Aβ y βCTF y aumenta los niveles de sAPPα en células deficientes de NPC1 que sobreexpresan APP. Consistentemente el tratamiento con Imatinib resultó en una disminución en el procesamiento amiloidogénico de APP en ratones nulos para NPC1. Por otra parte, también encontramos disminución de los niveles de βCTF en cultivos de neuronas corticales derivadas de ratones c-Ablfloxo/floxo Nestin Cre (neuronas nulas para c-Abl).Además, encontramos que c-Abl interactúa con APP y que el motivo -YENP- en la cola citoplásmica de APP es esencial para su interacción con c-Abl. Mediante el uso de imágenes de fluorescencia de vida media (FLIM), se observó que Imatinib redujo significativamente la interacción de APP con c-Abl. Sin embargo, más relevante fue que se observó que la inhibición de c-Abl reduce la interacción de APP con BACE1, lo que es consistente con que c-Abl potencia la interacción APP-BACE1 y promueve el procesamiento amiloidogénico de APP y la secreción de Aβ en modelos de NPC. En este trabajo, nosotros reportamos que específicamente la mutación Y682A afecta a la formación del complejo de APP con BACE1. Estos resultados dan nuevos antecedentes para comprender el papel desempeñado por c-Abl en su interacción con APP y en la progresión de la degeneración neuronal. Además, muestran el papel crucial que desempeña el residuo Tyr682 en el control del procesamiento de APP en las células.
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    Npc1 deficiency in the C57BL/6J genetic background enhances Niemann–Pick disease type C spleen pathology
    (2011) Parra Cares, Julio Alejandro; Klein, Andres D.; Castro, Juan Francisco; Morales France, María Gabriela; Mosqueira Montero, Matías José; Valencia Araya, Ilse; Cortés Mora, Víctor Antonio; Rigotti Rivera, Attilio; Zanlungo Matsuhiro, Silvana
    Niemann–Pick type C (NPC) disease is an autosomal recessive neurovisceral lipid storage disorder. The affected genes are NPC1 and NPC2. Mutations in either gene lead to intracellular cholesterol accumulation. There are three forms of the disease, which are categorized based on the onset and severity of the disease: the infantile form, in which the liver and spleen are severely affected, the juvenile form, in which the liver and brain are affected, and the adult form, which affects the brain. In mice, a spontaneous mutation in the Npc1 gene originated in the BALB/c inbred strain mimics the juvenile form of the disease. To study the influence of genetic background on the expression of NPC disease in mice, we transferred the Npc1 mutation from the BALB/c to C57BL/6J inbred background. We found that C57BL/6J-Npc1−/− mice present with a much more aggressive form of the disease, including a shorter lifespan than BALB/c-Npc1−/− mice. Surprisingly, there was no difference in the amount of cholesterol in the brains of Npc1−/− mice of either mouse strain. However, Npc1−/− mice with the C57BL/6J genetic background showed striking spleen damage with a marked buildup of cholesterol and phospholipids at an early age, which correlated with large foamy cell clusters. In addition, C57BL/6J Npc1−/− mice presented red cell abnormalities and abundant ghost erythrocytes that correlated with a lower hemoglobin concentration. We also found abnormalities in white cells, such as cytoplasmic granulation and neutrophil hypersegmentation that included lymphopenia and atypias. In conclusion, Npc1 deficiency in the C57BL6/J background is associated with spleen, erythrocyte, and immune system abnormalities that lead to a reduced lifespan.
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    Risk Factors and Pathogenesis of Cholesterol Gallstones: State of the Art
    (1999) Amigo, Ludwid; Zanlungo Matsuhiro, Silvana; Mendoza Vilches, Hegaly Lenny; Miquel P., Juan Francisco; Nervi, Flavio
    The aim of this article is to present an update of selected aspects of the pathogenesis and risk factors of cholesterol gallstones, a highly prevalent Western disease. The etiology of cholesterol cholelithiasis is considered to be multifactorial, with interaction of genetic and environmental factors. Mechanisms of cholesterol lithogenesis include biliary cholesterol hypersecretion, supersaturation and crystallization, stone formation and growth, and bile stasis within the gallbladder. Each of these various steps could be under genetic control and/or be influenced through intermediate pathogenic steps linked to a variety of environmental factors.
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    Vitamin E Dietary Supplementation Improves Neurological Symptoms and Decreases c-Abl/p73 Activation in Niemann-Pick C Mice
    (2014) Marín, Tamara; Contreras Soto, Pablo Andrés; Castro, Juan Francisco; Chamorro Veloso, David Daniel; Balboa Castillo, Elisa Ivana; Bosch Morató, Mónica; Muñoz, Francisco J.; Álvarez Rojas, Alejandra; Zanlungo Matsuhiro, Silvana