40 results on '"Gómez-Sintes, Raquel"'
Search Results
2. Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens
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Jiménez-Loygorri, Juan Ignacio, Benítez-Fernández, Rocío, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, and Boya, Patricia
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- 2023
- Full Text
- View/download PDF
3. Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens
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Ministerio de Ciencia e Innovación (España), University of Fribourg, Swiss National Science Foundation, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Benítez-Fernández, Rocío [0000-0003-3535-4370], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Benítez-Fernández, Rocío, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, Boya, Patricia, Ministerio de Ciencia e Innovación (España), University of Fribourg, Swiss National Science Foundation, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Benítez-Fernández, Rocío [0000-0003-3535-4370], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Benítez-Fernández, Rocío, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, and Boya, Patricia
- Abstract
Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases.
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- 2023
4. Autophagy in the eye: Development, degeneration, and aging
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Boya, Patricia, Esteban-Martínez, Lorena, Serrano-Puebla, Ana, Gómez-Sintes, Raquel, and Villarejo-Zori, Beatriz
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- 2016
- Full Text
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5. Ambra1 haploinsufficiency results in metabolic alterations and exacerbates age-associated retinal degeneration
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Villarejo-Zori, Beatriz [/0000-0002-5502-4793], Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Villarejo-Zori, Beatriz, Ramírez-Pardo, Ignacio, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Gómez-Sintes, Raquel, Boya, Patricia, Villarejo-Zori, Beatriz [/0000-0002-5502-4793], Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Villarejo-Zori, Beatriz, Ramírez-Pardo, Ignacio, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Gómez-Sintes, Raquel, and Boya, Patricia
- Abstract
Purpose: Retina is a highly complex and metabolically active tissue that sense the light. Persistent light-induced stimuli lead to constant turnover of the damaged cellular structures by proteostatic mechanisms such as autophagy. During aging there is a gradual decrease of autophagy which compromises retinal homeostasis and visual function. AMBRA1 (autophagy and beclin-1 regulator 1) is a key protein involved in the initiation phase of autophagy pathway. To further determine the importance of autophagy along aging, we will use Ambra1+/gt heterozygous mice, mimicking the decrease of autophagy during the aging process., Methods: We have used young (3 months), middle-aged (12 months) and old (25 months) Ambra1+/+ and Ambra1+/gt mice for this study. Visual function was determined by electroretinographic recordings (ERGs) along aging. Eyes were enucleated for histological porpoises or retinas were isolated for biochemical procedures. Retinal morphology and cellular components were assessed by immunofluorescence techniques on retinal cryosections or flatmounts. mRNA and protein lysates were obtained from isolated retinas. Metabolomic analyses were conducted using mass spectrometry and bioinformatic analysis was performed., Results: Ambra1+/gt retinas display a reduced autophagic flux at young without changes in the retinal integrity and function. However, aged Ambra1+/gt animals show an exacerbated loss of visual function also evidenced by morphological changes as increased gliosis, reduced nuclear density and cone number. Interestingly, we observed increased bipolar cell protrusions that might indicate the loss of synapsis between retinal layers. Partial loss of autophagy results in increased damaged mitochondria evidenced by a reduction in the mitochondrial membrane potential (MMP) in young age, higher oxidative stress at middle-aged and accumulation of mitochondrial mass in old Ambra1+/gt retinas. Finally, by metabolomics, we demonstrate marked metabolic alterations suggestive of defective oxidative metabolism in Ambra1+/gt animals at 1 year of age., Conclusions: Reduced autophagic response in Ambra1 haploinsufficient retinas leads to an exacerbated age-associated declines in retinal function, metabolic alterations and accumulation of damaged mitochondria.
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- 2022
6. Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration
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European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Mariño, Guillermo [0000-0003-1960-1677], de la Villa, P. [0000-0001-9856-6616], Fitze, Patrick S. [0000-0002-6298-2471], Fuentes, José M. [0000-0001-6910-2089], García-Escudero, Ramón [0000-0001-5640-6542], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Guillermo, de la Villa, P., Fitze, Patrick S., Fuentes, José M., García-Escudero, Ramón, Ferrington, Deborah A., Gómez-Sintes, Raquel, Boya, Patricia, European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Mariño, Guillermo [0000-0003-1960-1677], de la Villa, P. [0000-0001-9856-6616], Fitze, Patrick S. [0000-0002-6298-2471], Fuentes, José M. [0000-0001-6910-2089], García-Escudero, Ramón [0000-0001-5640-6542], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Guillermo, de la Villa, P., Fitze, Patrick S., Fuentes, José M., García-Escudero, Ramón, Ferrington, Deborah A., Gómez-Sintes, Raquel, and Boya, Patricia
- Abstract
Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we described a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging.
- Published
- 2022
7. Ambra1 haploinsufficiency results in metabolic alterations and exacerbates age‐associated retinal degeneration
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Villarejo‐Zori, Beatriz, primary, Ramírez‐Pardo, Ignacio, additional, Jiménez‐Loygorri, Juan Ignacio, additional, Sierra‐Filardi, Elena, additional, Alonso‐Gil, Sandra, additional, Gómez‐Sintes, Raquel, additional, and Boya, Patricia, additional
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- 2022
- Full Text
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8. Glycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer’s disease
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Fuster-Matanzo, Almudena, Jurado-Arjona, Jerónimo, Benvegnù, Stefano, García, Esther, Martín-Maestro, Patricia, Gómez-Sintes, Raquel, Hernández, Félix, and Ávila, Jesús
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- 2017
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9. Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice
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Gomez-Sintes, Raquel, Bortolozzi, Analia, Artigas, Francesc, and Lucas, José J.
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- 2014
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10. Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
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National Institutes of Health (US), JPB Foundation, Michael J. Fox Foundation for Parkinson's Research, Rainwater Charitable Foundation, Backus Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Gómez-Sintes, Raquel [0000-0003-2854-6964], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], McCabe, Mericka [0000-0001-6758-2330], Díaz, Antonio [0000-0001-7871-0828], Cotto-Rios, Xiomaris M. [0000-0003-0922-1857], Reynolds, Cara A. [0000-0003-3033-0089], De la Villa, Pedro [0000-0001-9856-6616], Macian, Fernando [0000-0003-2666-035X], Boya, Patricia [0000-0003-3045-951X], Gavathiotis, Evripidis [0000-0001-6319-8331], Cuervo, Ana Maria [0000-0002-0771-700X], Gómez-Sintes, Raquel, Xin, Qisheng, Jiménez-Loygorri, Juan Ignacio, McCabe, Mericka, Díaz, Antonio, Garner, Thomas P., Cotto-Rios, Xiomaris M., Wu, Yang, Dong, Shuxian, Reynolds, Cara A., Patel, Bindi, de la Villa, P., Macian, Fernando, Boya, Patricia, Gavathiotis, Evripidis, Cuervo, Ana Maria, National Institutes of Health (US), JPB Foundation, Michael J. Fox Foundation for Parkinson's Research, Rainwater Charitable Foundation, Backus Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Gómez-Sintes, Raquel [0000-0003-2854-6964], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], McCabe, Mericka [0000-0001-6758-2330], Díaz, Antonio [0000-0001-7871-0828], Cotto-Rios, Xiomaris M. [0000-0003-0922-1857], Reynolds, Cara A. [0000-0003-3033-0089], De la Villa, Pedro [0000-0001-9856-6616], Macian, Fernando [0000-0003-2666-035X], Boya, Patricia [0000-0003-3045-951X], Gavathiotis, Evripidis [0000-0001-6319-8331], Cuervo, Ana Maria [0000-0002-0771-700X], Gómez-Sintes, Raquel, Xin, Qisheng, Jiménez-Loygorri, Juan Ignacio, McCabe, Mericka, Díaz, Antonio, Garner, Thomas P., Cotto-Rios, Xiomaris M., Wu, Yang, Dong, Shuxian, Reynolds, Cara A., Patel, Bindi, de la Villa, P., Macian, Fernando, Boya, Patricia, Gavathiotis, Evripidis, and Cuervo, Ana Maria
- Abstract
Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.
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- 2021
11. Chaperone-mediated autophagy and disease: Implications for cancer and neurodegeneration
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National Institutes of Health (US), Ministerio de Ciencia e Innovación (España), Gómez-Sintes, Raquel [0000-0003-2854-6964], Arias, Esperanza [0000-0002-7836-5072], Gómez-Sintes, Raquel, Arias, Esperanza, National Institutes of Health (US), Ministerio de Ciencia e Innovación (España), Gómez-Sintes, Raquel [0000-0003-2854-6964], Arias, Esperanza [0000-0002-7836-5072], Gómez-Sintes, Raquel, and Arias, Esperanza
- Abstract
Chaperone-mediated autophagy (CMA) is a proteolytic process whereby selected intracellular proteins are degraded inside lysosomes. Owing to its selectivity, CMA participates in the modulation of specific regulatory proteins, thereby playing an important role in multiple cellular processes. Studies conducted over the last two decades have enabled the molecular characterization of this autophagic pathway and the design of specific experimental models, and have underscored the importance of CMA in a range of physiological processes beyond mere protein quality control. Those findings also indicate that decreases in CMA function with increasing age may contribute to the pathogenesis of age-associated diseases, including neurodegeneration and cancer. In the context of neurological diseases, CMA impairment is thought to contribute to the accumulation of misfolded/aggregated proteins, a process central to the pathogenesis of neurodegenerative diseases. CMA therefore constitutes a potential therapeutic target, as its induction accelerates the clearance of pathogenic proteins, promoting cell survival. More recent evidence has highlighted the important and complex role of CMA in cancer biology. While CMA induction may limit tumor development, experimental evidence also indicates that inhibition of this pathway can attenuate the growth of established tumors and improve the response to cancer therapeutics. Here, we describe and discuss the evidence supporting a role of impaired CMA function in neurodegeneration and cancer, as well as future research directions to evaluate the potential of this pathway as a target for the prevention and treatment of these diseases.
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- 2021
12. Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus
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Engel, Tobias, Gómez-Sintes, Raquel, Alves, Mariana, Jimenez-Mateos, Eva M., Fernández-Nogales, Marta, Sanz-Rodriguez, Amaya, Morgan, James, Beamer, Edward, Rodríguez-Matellán, Alberto, Dunleavy, Mark, Sano, Takanori, Avila, Jesus, Medina, Miguel, Hernandez, Felix, Lucas, José J., and Henshall, David C.
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- 2018
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13. HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
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Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], Trifunovic, Dragana [0000-0003-3168-4196], Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunovic, Dragana, Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], Trifunovic, Dragana [0000-0003-3168-4196], Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, and Trifunovic, Dragana
- Abstract
Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways,including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.
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- 2020
14. Ambra1 and its role during physiological ageing in the retina
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Boya, Patricia [0000-0003-3045-951X], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia, Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, Boya, Patricia [0000-0003-3045-951X], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia, Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, and Gómez-Sintes, Raquel
- Abstract
Purpose : Ambra1 (activating-molecule in Beclin-1-regulated autophagy) is a protein that regulates the early stages of autophagy initiation. Ambra1 haploinsufficiency is linked to autophagy under several pathological conditions such as Alzheimer Disease, autism or multiple system atrophy. In the retina, there is a decline in the autophagy response upon ageing thus we aimed to test if Ambragt/+ haploinsufficiency might affect retinal ageing., Methods : As Ambra1 homozigous animals are embryonic lethal, we have analised the phenotype of Ambra1gt/+ during aging and compared with Ambra1+/+ litermates. We have assessed retinal morphology and function with ERG in animals up to 24 months as well as compared the metabolic profile using mass spectrometry., Results : Our results show that Ambra1gt/+ display premature death in comparison to control littermates. We also observe symptoms of premature retinal ageing in Ambra1gt/+ mice at 15 months old. This tendency was increased in geriatric animals (>20 months) as Ambra1gt/+ displayed increased inflammatory response and a reduction in the photoreceptor layer thickness. Finally, aged Ambra1gt/+ mice displayed a different metabolic signature indicating a misbalance in the purine metabolism and redox status., Conclusions : This data suggest that autophagy deficiency results in a pro-ageing phenotype and impair retinal homeostasis and metabolism.
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- 2020
15. Ambra1 and its role during physiological ageing in the retina
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Boya, Patricia, Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, Boya, Patricia [0000-0003-3045-951X], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia, and Gómez-Sintes, Raquel
- Abstract
from 2020 ARVO Annual Meeting, canceled because of COVID-19, Purpose : Ambra1 (activating-molecule in Beclin-1-regulated autophagy) is a protein that regulates the early stages of autophagy initiation. Ambra1 haploinsufficiency is linked to autophagy under several pathological conditions such as Alzheimer Disease, autism or multiple system atrophy. In the retina, there is a decline in the autophagy response upon ageing thus we aimed to test if Ambragt/+ haploinsufficiency might affect retinal ageing., Methods : As Ambra1 homozigous animals are embryonic lethal, we have analised the phenotype of Ambra1gt/+ during aging and compared with Ambra1+/+ litermates. We have assessed retinal morphology and function with ERG in animals up to 24 months as well as compared the metabolic profile using mass spectrometry., Results : Our results show that Ambra1gt/+ display premature death in comparison to control littermates. We also observe symptoms of premature retinal ageing in Ambra1gt/+ mice at 15 months old. This tendency was increased in geriatric animals (>20 months) as Ambra1gt/+ displayed increased inflammatory response and a reduction in the photoreceptor layer thickness. Finally, aged Ambra1gt/+ mice displayed a different metabolic signature indicating a misbalance in the purine metabolism and redox status., Conclusions : This data suggest that autophagy deficiency results in a pro-ageing phenotype and impair retinal homeostasis and metabolism.
- Published
- 2020
16. Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus
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Ettcheto, Miren, Junyent, Felix, de Lemos, Luisa, Pallas, Merce, Folch, Jaume, Beas-Zarate, Carlos, Verdaguer, Ester, Gómez-Sintes, Raquel, Lucas, José J., Auladell, Carme, and Camins, Antoni
- Published
- 2015
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17. Chaperone-mediated autophagy and disease: Implications for cancer and neurodegeneration
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Gómez-Sintes, Raquel, primary and Arias, Esperanza, additional
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- 2021
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18. NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy
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Gómez-Sintes, Raquel and Lucas, José J.
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- 2010
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19. Lysosomal membrane permeabilization and cell death
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Wang, Fengjuan, primary, Gómez-Sintes, Raquel, additional, and Boya, Patricia, additional
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- 2018
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20. Standard Assays for the Study of Autophagy in the Ex Vivo Retina
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Consejo Superior de Investigaciones Científicas (España), Ministerio de Economía y Competitividad (España), European Commission, Gómez-Sintes, Raquel, Villarejo-Zori, Beatriz, Serrano-Puebla, Ana, Esteban-Martínez, Lorena, Sierra-Filardi, Elena, Ramírez-Pardo, Ignacio, Rodríguez-Muela, N., Boya, Patricia, Consejo Superior de Investigaciones Científicas (España), Ministerio de Economía y Competitividad (España), European Commission, Gómez-Sintes, Raquel, Villarejo-Zori, Beatriz, Serrano-Puebla, Ana, Esteban-Martínez, Lorena, Sierra-Filardi, Elena, Ramírez-Pardo, Ignacio, Rodríguez-Muela, N., and Boya, Patricia
- Abstract
Autophagy is a catabolic pathway that mediates the degradation and recycling of intracellular components, and is a key player in a variety of physiological processes in cells and tissues. Recent studies of autophagy in the eye suggest that this pathway is fundamental for the preservation of retinal homeostasis. Given its accessible location outside the brain, the retina is an ideal organ in which to study the central nervous system and a wide range of neuronal processes, from development to neurodegeneration. Here we review several methods used to assess autophagy in the retina in both physiological and pathological conditions.
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- 2017
21. Standard Assays for the Study of Autophagy in the Ex Vivo Retina
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Gómez-Sintes, Raquel, primary, Villarejo-Zori, Beatriz, additional, Serrano-Puebla, Ana, additional, Esteban-Martínez, Lorena, additional, Sierra-Filardi, Elena, additional, Ramírez-Pardo, Ignacio, additional, Rodríguez-Muela, Natalia, additional, and Boya, Patricia, additional
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- 2017
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22. Lysosomal cell death mechanisms in aging
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Gómez-Sintes, Raquel, primary, Ledesma, María Dolores, additional, and Boya, Patricia, additional
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- 2016
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23. Glycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer’s disease
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Fuster-Matanzo, Almudena, primary, Jurado-Arjona, Jerónimo, additional, Benvegnù, Stefano, additional, García, Esther, additional, Martín-Maestro, Patricia, additional, Gómez-Sintes, Raquel, additional, Hernández, Félix, additional, and Ávila, Jesús, additional
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- 2016
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24. Glycogen synthase kinase-3ß regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer¿s disease
- Author
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Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Fundación Botín, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Ramón Areces, Fuster-Matanzo, Almudena, Jurado-Arjona, Jerónimo, Benvegnú, Stefano, García, Esther, Martín-Maestro, Patricia, Gómez-Sintes, Raquel, Hernández, Félix, Ávila, Jesús, Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Fundación Botín, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Ramón Areces, Fuster-Matanzo, Almudena, Jurado-Arjona, Jerónimo, Benvegnú, Stefano, García, Esther, Martín-Maestro, Patricia, Gómez-Sintes, Raquel, Hernández, Félix, and Ávila, Jesús
- Abstract
Glycogen synthase kinase-3b (GSK-3b) is a serine-threonine kinase implicated in multiple processes and signaling pathways. Its dysregulation is associated with different pathological conditions including Alzheimer’s disease (AD). Here we demonstrate how changes in GSK-3b activity and/or levels regulate the production and subsequent secretion of fractalkine, a chemokine involved in the immune response that has been linked to AD and to other different neurological disorders. Treatment of primary cultured neurons with GSK-3b inhibitors such as lithium and AR-A014418 decreased full-length fractalkine in total cell extracts. Opposite effects were observed after neuron transduction with a lentiviral vector overexpressing the kinase. Biotinylation assays showed that those changes mainly affect the plasma membrane-associated form of the protein, an observation that positively correlates with changes in the levels of its soluble form. These effects were confirmed in lithium-treated wild type (wt) mice and in GSK-3b transgenic animals, as well as in brain samples from AD patients, evident as age-dependent (animals) or Braak stage dependent changes (humans) in both the membrane-bound and the soluble forms of the protein. Further immunohistochemical analyses demonstrated how GSK-3b exerts these effects by affecting the trafficking of the chemokine from the Golgi to the plasma membrane, in different and opposite ways when the levels/activity of the kinase are increased or decreased. This work provides for the first time a mechanism linking GSK-3b and fractalkine both in vitro and in vivo, with important implications for neurological disorders and especially for AD, in which levels of this chemokine might be useful as a diagnostic tool.
- Published
- 2016
25. Lysosomal cell death mechanisms in aging
- Author
-
Ministerio de Economía y Competitividad (España), Gómez-Sintes, Raquel, Ledesma, M. Dolores, Boya, Patricia, Ministerio de Economía y Competitividad (España), Gómez-Sintes, Raquel, Ledesma, M. Dolores, and Boya, Patricia
- Abstract
Lysosomes are degradative organelles essential for cell homeostasis that regulate a variety of processes, from calcium signaling and nutrient responses to autophagic degradation of intracellular components. Lysosomal cell death is mediated by the lethal effects of cathepsins, which are released into the cytoplasm following lysosomal damage. This process of lysosomal membrane permeabilization and cathepsin release is observed in several physiopathological conditions and plays a role in tissue remodeling, the immune response to intracellular pathogens and neurodegenerative diseases. Many evidences indicate that aging strongly influences lysosomal activity by altering the physical and chemical properties of these organelles, rendering them more sensitive to stress. In this review we focus on how aging alters lysosomal function and increases cell sensitivity to lysosomal membrane permeabilization and lysosomal cell death, both in physiological conditions and age-related pathologies.
- Published
- 2016
26. Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus
- Author
-
Generalitat de Catalunya, Consejo Nacional de Ciencia y Tecnología (México), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Ettcheto, Miren, Gómez-Sintes, Raquel, Lucas, José Javier, Camins, Antoni, Generalitat de Catalunya, Consejo Nacional de Ciencia y Tecnología (México), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Ettcheto, Miren, Gómez-Sintes, Raquel, Lucas, José Javier, and Camins, Antoni
- Abstract
© 2014, Springer Science+Business Media New York. The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the up-regulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase-4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy.
- Published
- 2015
27. Mice with a naturally occurring DISC1 mutation display a broad spectrum of behaviors associated to psychiatric disorders
- Author
-
Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundación Ramón Areces, Gómez-Sintes, Raquel, Kvajo, Mirna, Gogos, Josep A., Lucas, José Javier, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundación Ramón Areces, Gómez-Sintes, Raquel, Kvajo, Mirna, Gogos, Josep A., and Lucas, José Javier
- Abstract
Disrupted in schizophrenia-1 (DISC1) gene is associated with several neuropsychiatric disorders as it is disrupted by a balanced translocation involving chromosomes 1 and 11 in a large Scottish pedigree with high prevalence of schizophrenia, bipolar disorder and major depression. Since its identification, several mouse models with DISC1 genetic modifications have been generated using different approaches. Interestingly, a natural deletion of 25bp in the 129 mouse strain alters the DISC1 gene reading frame leading to a premature stop codon very close to the gene breakpoint in the mutant allele of the Scottish family. In the present study we confirmed that the 129DISC1Del mutation results in reduced level of full length DISC1 in hippocampus of heterozygous mice and we have characterized the behavioral consequences of heterozygous 129DISC1Del mutation in a mixed B6129 genetic background. We found alterations in spontaneous locomotor activity (hyperactivity in males and hypoactivity in females), deficits in pre-pulse inhibition (PPI) and also increased despair behavior in heterozygous 129DISC1Del mice, thus reproducing typical behaviors associated to psychiatric disorders. Since this mouse strain is widely and commercially available, we propose it as an amenable tool to study DISC1-related biochemical alterations and psychiatric behaviors. © 2014 Gómez-Sintes, Kvajo, Gogos and Lucas.
- Published
- 2014
28. Consecuencias neurológicas de la inhibición sostenida de GSK-3 en cerebro adulto
- Author
-
Gómez Sintes, Raquel, Lucas Lozano, José Javier, and Universidad Autónoma de Madrid. Departamento de Biología Molecular
- Subjects
Diabetes - Tesis doctorales ,Esquizofrenia - Tesis doctorales ,Huntington, Enfermedad de - Tesis doctorales ,Alzheimer, Enfermedad de - Tesis doctorales ,Trastornos bipolares - Tesis doctorales - Abstract
Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 11-septiembre-09
- Published
- 2009
29. Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus
- Author
-
Ettcheto, Miren, primary, Junyent, Felix, additional, de Lemos, Luisa, additional, Pallas, Merce, additional, Folch, Jaume, additional, Beas-Zarate, Carlos, additional, Verdaguer, Ester, additional, Gómez-Sintes, Raquel, additional, Lucas, José J., additional, Auladell, Carme, additional, and Camins, Antoni, additional
- Published
- 2014
- Full Text
- View/download PDF
30. Neuronal Apoptosis and Motor Deficits in Mice with Genetic Inhibition of GSK-3 Are Fas-Dependent
- Author
-
Gómez-Sintes, Raquel, Lucas, José Javier, Gómez-Sintes, Raquel, and Lucas, José Javier
- Abstract
Glycogen synthase kinase-3 (GSK-3) inhibitors have been postulated as useful therapeutic tools for the treatment of chronic neurodegenerative and neuropsychiatric diseases. Nevertheless the clinical use of these inhibitors has been limited by their common side effects. Lithium, a non-selective GSK-3 inhibitor has been classically administered to treat bipolar patients but its prescription is decreasing due to its frequent side effects such as hand tremor. This toxicity seems to be higher in the elderly and a clinical trial with lithium for Alzheimer's disease was stopped due to high rate of discontinuation. We have previously described a mechanism for the adverse effects of chronic lithium that involves neuronal apoptosis via Fas signaling. As lithium inhibits many other enzymatic activities such as inositol monophosphatase and histone deacetylase, here we aim to genetically test whether GSK-3 inhibition induces those adverse effects through Fas receptor. For this purpose we took advantage of a transgenic mouse line with decreased GSK-3 activity (Tet/DN-GSK-3 mice) that shows increased rate of neuronal apoptosis as well as motor deficits and brought it to a Fas deficient background (lpr mice). We found that apoptosis induced by GSK-3 inhibition was absent in Fas deficient background. Interestingly, motor deficits were also absent in Fas deficient Tet/DN-GSK-3 mice. These results demonstrate that Fas signaling contributes to the neurological toxicity of GSK-3 inhibition and suggest that a combination of GSK-3 inhibitors with blockers of Fas signaling could help to improve the application of GSK-3 inhibitors to clinics. © 2013 Gómez-Sintes, Lucas.
- Published
- 2013
31. GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration
- Author
-
Gómez-Sintes, Raquel, Hernández Pérez, Félix, Lucas, José Javier, Ávila, Jesús, Gómez-Sintes, Raquel, Hernández Pérez, Félix, Lucas, José Javier, and Ávila, Jesús
- Abstract
Increased GSK-3 activity is believed to contribute to the etiology of chronic disorders like Alzheimer’s disease (AD), schizophrenia, diabetes, and some types of cancer, thus supporting therapeutic potential of GSK-3 inhibitors. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this review we have focused on the relevance of these mouse models for the study of the role of GSK-3 in apoptosis. GSK-3 is involved in two apoptotic pathways, intrinsic and extrinsic pathways, and plays opposite roles depending on the apoptotic signaling process that is activated. It promotes cell death when acting through intrinsic pathway and plays an anti-apoptotic role if the extrinsic pathway is occurring. It is important to dissect this duality since, among the diseases in which GSK-3 is involved, excessive cell death is crucial in some illnesses like neurodegenerative diseases, while a deficient apoptosis is occurring in others such as cancer or autoimmune diseases. The clinical application of a classical GSK-3 inhibitor, lithium, is limited by its toxic consequences, including motor side effects. Recently, the mechanism leading to activation of apoptosis following chronic lithium administration has been described. Understanding this mechanism could help to minimize side effects and to improve application of GSK-3 inhibitors to the treatment of AD and to extend the application to other diseases.
- Published
- 2011
32. Neuronal Apoptosis and Motor Deficits in Mice with Genetic Inhibition of GSK-3 Are Fas-Dependent
- Author
-
Gómez-Sintes, Raquel, primary and Lucas, José J., additional
- Published
- 2013
- Full Text
- View/download PDF
33. GSK-3 mouse models to study neuronal apoptosis and neurodegeneration
- Author
-
Gómez-Sintes, Raquel, primary
- Published
- 2011
- Full Text
- View/download PDF
34. Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice
- Author
-
Gómez-Sintes, Raquel, primary, Hernández, Félix, additional, Bortolozzi, Analía, additional, Artigas, Francesc, additional, Avila, Jesús, additional, Zaratin, Paola, additional, Gotteland, Jean Pierre, additional, and Lucas, José J, additional
- Published
- 2007
- Full Text
- View/download PDF
35. Mice with a naturally occurring DISC1 mutation display a broad spectrum of behaviors associated to psychiatric disorders.
- Author
-
Gómez-Sintes, Raquel, Kvajo, Mirna, Gogos, Joseph A., and Lucas, José J.
- Subjects
ANIMAL disease models ,PATHOLOGICAL psychology ,SCHIZOPHRENIA ,NEUROBEHAVIORAL disorders ,BIPOLAR disorder ,HIPPOCAMPUS (Brain) - Abstract
Disrupted in schizophrenia-1 (DISC1) gene is associated with several neuropsychiatric disorders as it is disrupted by a balanced translocation involving chromosomes 1 and 11 in a large Scottish pedigree with high prevalence of schizophrenia, bipolar disorder and major depression. Since its identification, several mouse models with DISC1 genetic modifications have been generated using different approaches. Interestingly, a natural deletion of 25bp in the 129 mouse strain alters the DISC1 gene reading frame leading to a premature stop codon very close to the gene breakpoint in the mutant allele of the Scottish family. In the present study we confirmed that the 129DISC1
Del mutation results in reduced level of full length DISC1 in hippocampus of heterozygous mice and we have characterized the behavioral consequences of heterozygous 129DISC1Del mutation in a mixed B6129 genetic background. We found alterations in spontaneous locomotor activity (hyperactivity in males and hypoactivity in females), deficits in pre-pulse inhibition (PPI) and also increased despair behavior in heterozygous 129DISC1Del mice, thus reproducing typical behaviors associated to psychiatric disorders. Since this mouse strain is widely and commercially available, we propose it as an amenable tool to study DISC1-related biochemical alterations and psychiatric behaviors. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
36. Glycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer's disease
- Author
-
Fuster-Matanzo, Almudena, Jurado-Arjona, Jerónimo, Benvegnù, Stefano, García, Esther, Martín-Maestro, Patricia, Gómez-Sintes, Raquel, Hernández, Félix, and Ávila, Jesús
- Subjects
Glycogen Synthase Kinase 3 beta ,Chemokine CX3CL1 ,GSK-3β ,Cell Membrane ,Golgi Apparatus ,Fractalkine ,3. Good health ,Mice, Inbred C57BL ,Protein Transport ,Solubility ,Alzheimer Disease ,rab GTP-Binding Proteins ,Rab8 ,Golgi network ,Animals ,Humans ,Transport Vesicles ,Alzheimer’s disease ,Protein Binding - Abstract
Glycogen synthase kinase-3β (GSK-3β) is a serine-threonine kinase implicated in multiple processes and signaling pathways. Its dysregulation is associated with different pathological conditions including Alzheimer's disease (AD). Here we demonstrate how changes in GSK-3β activity and/or levels regulate the production and subsequent secretion of fractalkine, a chemokine involved in the immune response that has been linked to AD and to other different neurological disorders. Treatment of primary cultured neurons with GSK-3β inhibitors such as lithium and AR-A014418 decreased full-length fractalkine in total cell extracts. Opposite effects were observed after neuron transduction with a lentiviral vector overexpressing the kinase. Biotinylation assays showed that those changes mainly affect the plasma membrane-associated form of the protein, an observation that positively correlates with changes in the levels of its soluble form. These effects were confirmed in lithium-treated wild type (wt) mice and in GSK-3β transgenic animals, as well as in brain samples from AD patients, evident as age-dependent (animals) or Braak stage dependent changes (humans) in both the membrane-bound and the soluble forms of the protein. Further immunohistochemical analyses demonstrated how GSK-3β exerts these effects by affecting the trafficking of the chemokine from the Golgi to the plasma membrane, in different and opposite ways when the levels/activity of the kinase are increased or decreased. This work provides for the first time a mechanism linking GSK-3β and fractalkine both in vitro and in vivo, with important implications for neurological disorders and especially for AD, in which levels of this chemokine might be useful as a diagnostic tool.
37. HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
- Author
-
Jerome E. Roger, Angela Armento, Eleni Petridou, Patricia Boya, Marijana Samardzija, Raquel Gómez-Sintes, Eberhart Zrenner, Marius Ueffing, Dragana Trifunović, Christian Grimm, Wadood Haq, Andrea Corna, Mohamed Ali Jarboui, Günther Zeck, François Paquet-Durand, Pedro de la Villa, University of Zurich, Trifunović, Dragana, Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunovic, Dragana, Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], and Trifunovic, Dragana [0000-0003-3168-4196]
- Subjects
10018 Ophthalmology Clinic ,MAPK/ERK pathway ,Programmed cell death ,genetic structures ,610 Medicine & health ,Biology ,Article ,Photoreceptor cell ,1307 Cell Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Retinitis pigmentosa ,1312 Molecular Biology ,medicine ,Animals ,Molecular Biology ,030304 developmental biology ,Mice, Inbred C3H ,0303 health sciences ,Autophagy ,Retinal ,Cell Biology ,medicine.disease ,Cone cell ,ddc ,3. Good health ,Cell biology ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,Disease Models, Animal ,Neuroprotective Agents ,medicine.anatomical_structure ,Histone ,Gene Expression Regulation ,chemistry ,Intravitreal Injections ,Retinal Cone Photoreceptor Cells ,biology.protein ,sense organs ,Neurological disorders ,Retinitis Pigmentosa ,030217 neurology & neurosurgery ,Neuroscience - Abstract
16 p.-7 fig., Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways,including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages., This work was supported by the ProRetina foundation,the Kerstan Foundation, Deutsche Forschungsgemeinschaft (DFGTR 1238/4-1), Swiss National Science Foundation (31003A_173008),BMBF (FKZ: 01EK1613E), and GC2018-098557-B-I00 from MCIU/AEI/FEDER, UE. RGS is a recipient of a JIN grant RTI2018-098990- J-I00 from MCIU, Spain.
- Published
- 2020
38. Ambra1 haploinsufficiency in cd1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration
- Author
-
Ignacio Ramírez-Pardo, Beatriz Villarejo-Zori, Juan Ignacio Jiménez-Loygorri, Elena Sierra-Filardi, Sandra Alonso-Gil, Guillermo Mariño, Pedro de la Villa, Patrick S Fitze, José Manuel Fuentes, Ramón García-Escudero, Deborah A. Ferrington, Raquel Gomez-Sintes, Patricia Boya, European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Mariño, Guillermo [0000-0003-1960-1677], de la Villa, P. [0000-0001-9856-6616], Fitze, Patrick S. [0000-0002-6298-2471], Fuentes, José M. [0000-0001-6910-2089], García-Escudero, Ramón [0000-0001-5640-6542], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Ramírez-Pardo, Ignacio, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Mariño, Guillermo, de la Villa, P., Fitze, Patrick S., Fuentes, José M., García-Escudero, Ramón, Gómez-Sintes, Raquel, and Boya, Patricia
- Subjects
Aging ,Retinal pigment ,Autophagy ,Metabolic alterations ,Cell Biology ,AMBRA1 ,Neurodegeneration ,Molecular Biology ,Retina ,Epithelium - Abstract
22 p.-9 fig., Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we described a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging., This work was supported by the H2020 Excellent Science [No. 765912]; Instituto de Salud Carlos III,CiberNed [CB06/05/0041]; Spanish Ministry of Science and Innovation [RTI2018-098990-J-I00]; Spanish Ministry of Science and Innovation [PGC2018-098557-B-I00].
- Published
- 2022
39. Chaperone-mediated autophagy and disease: Implications for cancer and neurodegeneration
- Author
-
Esperanza Arias, Raquel Gomez-Sintes, National Institutes of Health (US), Ministerio de Ciencia e Innovación (España), Gómez-Sintes, Raquel, Arias, Esperanza, Gómez-Sintes, Raquel [0000-0003-2854-6964], and Arias, Esperanza [0000-0002-7836-5072]
- Subjects
Clinical Biochemistry ,Context (language use) ,Chaperone-Mediated Autophagy ,Disease ,Protein degradation ,Biology ,medicine.disease_cause ,Biochemistry ,Article ,Aggregation ,Chaperone-mediated autophagy ,Neoplasms ,Chaperones ,medicine ,Autophagy ,Humans ,Molecular Biology ,health care economics and organizations ,Neurodegeneration ,Cancer ,Neurodegenerative Diseases ,General Medicine ,medicine.disease ,humanities ,Cell biology ,Tumorigenesis ,Molecular Medicine ,Carcinogenesis ,Lysosomes ,Molecular Chaperones - Abstract
14 p.-3 fig.-1 tab., Chaperone-mediated autophagy (CMA) is a proteolytic process whereby selected intracellular proteins are degraded inside lysosomes. Owing to its selectivity, CMA participates in the modulation of specific regulatory proteins, thereby playing an important role in multiple cellular processes. Studies conducted over the last two decades have enabled the molecular characterization of this autophagic pathway and the design of specific experimental models, and have underscored the importance of CMA in a range of physiological processes beyond mere protein quality control. Those findings also indicate that decreases in CMA function with increasing age may contribute to the pathogenesis of age-associated diseases, including neurodegeneration and cancer. In the context of neurological diseases, CMA impairment is thought to contribute to the accumulation of misfolded/aggregated proteins, a process central to the pathogenesis of neurodegenerative diseases. CMA therefore constitutes a potential therapeutic target, as its induction accelerates the clearance of pathogenic proteins, promoting cell survival. More recent evidence has highlighted the important and complex role of CMA in cancer biology. While CMA induction may limit tumor development, experimental evidence also indicates that inhibition of this pathway can attenuate the growth of established tumors and improve the response to cancer therapeutics. Here, we describe and discuss the evidence supporting a role of impaired CMA function in neurodegeneration and cancer, as well as future research directions to evaluate the potential of this pathway as a target for the prevention and treatment of these diseases., Work in EA laboratory is supported by the National Institutes of Health: DK124308, P30DK041296 (P&F) and P30AG038072 (P&F). RGS is recipient of the Spanish Ministry of Science and Innovation grant RTI2018-098990-J-I00.
- Published
- 2021
40. Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
- Author
-
Raquel Gomez-Sintes, Qisheng Xin, Juan Ignacio Jimenez-Loygorri, Mericka McCabe, Antonio Diaz, Thomas P. Garner, Xiomaris M. Cotto-Rios, Yang Wu, Shuxian Dong, Cara A. Reynolds, Bindi Patel, Pedro de la Villa, Fernando Macian, Patricia Boya, Evripidis Gavathiotis, Ana Maria Cuervo, National Institutes of Health (US), JPB Foundation, Michael J. Fox Foundation for Parkinson's Research, Rainwater Charitable Foundation, Backus Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Gómez-Sintes, Raquel, Jiménez-Loygorri, Juan Ignacio, McCabe, Mericka, Díaz, Antonio, Cotto-Rios, Xiomaris M., Reynolds, Cara A., De la Villa, Pedro, Macian, Fernando, Boya, Patricia, Gavathiotis, Evripidis, and Cuervo, Ana Maria
- Subjects
Mice ,Multidisciplinary ,Retinoic Acid Receptor alpha ,Retinal Degeneration ,Autophagy ,General Physics and Astronomy ,Animals ,Chaperone-Mediated Autophagy ,General Chemistry ,Co-Repressor Proteins ,General Biochemistry, Genetics and Molecular Biology ,Retinitis Pigmentosa - Abstract
18 p.-8 fig., Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration., This work was supported by National Institutes of Health grants AG054108, AG021904, and AG017617 (to AMC) and AG038072 (to AMC, FM, and EG), the JPB Foundation (to AMC), the Michael J. Fox Foundation (to AMC and EG), the Rainwater Charitable Foundation (to AMC and EG) and the Backus Foundation (to AMC). Chemical synthesis, NMR and MS data were in part supported by NIH awards P30 CA013330 and 1S10OD016305. Research in PB and RGS lab is funded by Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018-098557-B-I00 to PB and RTI2018-098990-J-I00 to RGS. CAR was supported by T32 GM007491 and MM by T32 AG023475.
- Published
- 2021
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