14 results on '"Leiva-Rodríguez, Tatiana"'
Search Results
2. ATG5 overexpression is neuroprotective and attenuates cytoskeletal and vesicle-trafficking alterations in axotomized motoneurons
- Author
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Leiva-Rodríguez, Tatiana, Romeo-Guitart, David, Marmolejo-Martínez-Artesero, Sara, Herrando-Grabulosa, Mireia, Bosch, Assumpció, Forés, Joaquim, and Casas, Caty
- Published
- 2018
- Full Text
- View/download PDF
3. SIRT1 activation with neuroheal is neuroprotective but SIRT2 inhibition with AK7 is detrimental for disconnected motoneurons
- Author
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Romeo-Guitart, David, Leiva-Rodríguez, Tatiana, Espinosa-Alcantud, María, Sima, Núria, Vaquero, Alejandro, Domínguez- Martín, Helena, Ruano, Diego, and Casas, Caty
- Published
- 2018
- Full Text
- View/download PDF
4. GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy
- Author
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Leiva-Rodríguez, Tatiana, primary, Romeo-Guitart, David, additional, Herrando-Grabulosa, Mireia, additional, Muñoz-Guardiola, Pau, additional, Polo, Miriam, additional, Bañuls, Celia, additional, Petegnief, Valerie, additional, Bosch, Assumpció, additional, Lizcano, Jose Miguel, additional, Apostolova, Nadezda, additional, Forés, Joaquim, additional, and Casas, Caty, additional
- Published
- 2021
- Full Text
- View/download PDF
5. Descrita una nova via molecular que millora la regeneració nerviosa a través de la inducció de l'autofàgia
- Author
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Romeo-Guitart, David, Leiva-Rodríguez, Tatiana, Forés Vineta, Joaquim, and Casas Louzao, Caty
- Abstract
L'autofàgia és un mecanisme cel·lular endogen amb doble funció: pot intervenir en els processos de mort cel·lular i apoptosis però també actuar en la regeneració de la cèl·lula. Un equip de recerca conjunt de l'Institut de Neurociència de la UAB i de l'Hospital Clínic ha dut a terme un estudi sobre l'efecte de la inducció de l'autofàgia per manipulació genètica i farmacològica en la regeneració del nervi motor després de sofrir una lesió. Els resultats han permès descobrir una nova diana terapèutica en observar que es pot accelerar el procés regeneratiu de la cèl·lula, la qual cosa afavoreix la recuperació funcional. La autofagia es un mecanismo celular endógeno con doble función: puede intervenir en los procesos de muerte celular y apoptosis pero también actuar en la regeneración de la célula. Un equipo de investigación conjunto del Instituto de Neurociencias de la UAB y del Hospital Clínico ha llevado a cabo un estudio sobre el efecto de la inducción de la autofagia por manipulación genética y farmacológica en la regeneración del nervio motor tras sufrir una lesión. Los resultados han permitido descubrir una nueva diana terapéutica al observar que se puede acelerar el proceso regenerativo de la célula, lo que favorece la recuperación funcional.
- Published
- 2021
6. Grp78 overexpression triggers PINK1-IP3R-mediated neuroprotective mitophagy
- Author
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Leiva-Rodríguez, Tatiana, Romeo-Guitart, David, Herrando-Grabulosa, Mireia, Muñoz-Guardiola, Pau, Polo, Miriam, Bañuls, Celia, Petegnief, Valerie, Bosch i Merino, Assumpció, Lizcano de Vega, José Miguel, Apostolova, Nadezda, Forés Vineta, Joaquim, Casas Louzao, Caty, Leiva-Rodríguez, Tatiana, Romeo-Guitart, David, Herrando-Grabulosa, Mireia, Muñoz-Guardiola, Pau, Polo, Miriam, Bañuls, Celia, Petegnief, Valerie, Bosch i Merino, Assumpció, Lizcano de Vega, José Miguel, Apostolova, Nadezda, Forés Vineta, Joaquim, and Casas Louzao, Caty
- Abstract
Altres ajuts: Marató de TV3 (201607.10), An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurode-generative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tag-ging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.
- Published
- 2021
7. Grp78 overexpression triggers pink1-ip3 r-mediated neuroprotective mitophagy
- Author
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Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Leiva-Rodríguez, Tatiana, Romeo-Guitart, David, Herrando-Grabulosa, Mireia, Muñoz-Guardiola, Pau, Polo, Miriam, Bañuls, Celia, Petegnief, Valérie, Bosch, Assumpció, Lizcano, José M., Apostolova, Nadezda, Forés, Joaquim, Casas, Caty, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Leiva-Rodríguez, Tatiana, Romeo-Guitart, David, Herrando-Grabulosa, Mireia, Muñoz-Guardiola, Pau, Polo, Miriam, Bañuls, Celia, Petegnief, Valérie, Bosch, Assumpció, Lizcano, José M., Apostolova, Nadezda, Forés, Joaquim, and Casas, Caty
- Abstract
An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurode-generative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tag-ging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.
- Published
- 2021
8. Neuroprotective drug for nerve trauma revealed using artificial intelligence
- Author
-
Fundació La Marató de TV3, Ministerio de Economía y Competitividad (España), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), European Commission, Romeo-Guitart, David [0000-0003-3368-9302], Leiva-Rodríguez, Tatiana [0000-0003-0359-0045], Navarro, Xavier[0000-0001-9849-902X], Casas, Caty [0000-0002-2273-6321], Romeo-Guitart, David, Forés, Joaquim, Herrando-Grabulosa, Mireia, Valls, Raquel, Leiva-Rodríguez, Tatiana, Galea, Elena, González-Pérez, Francisco, Navarro, Xavier, Petegnief, Valérie, Bosch, Assumpció, Coma, Mireia, Mas, José Manuel, Casas, Caty, Fundació La Marató de TV3, Ministerio de Economía y Competitividad (España), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), European Commission, Romeo-Guitart, David [0000-0003-3368-9302], Leiva-Rodríguez, Tatiana [0000-0003-0359-0045], Navarro, Xavier[0000-0001-9849-902X], Casas, Caty [0000-0002-2273-6321], Romeo-Guitart, David, Forés, Joaquim, Herrando-Grabulosa, Mireia, Valls, Raquel, Leiva-Rodríguez, Tatiana, Galea, Elena, González-Pérez, Francisco, Navarro, Xavier, Petegnief, Valérie, Bosch, Assumpció, Coma, Mireia, Mas, José Manuel, and Casas, Caty
- Abstract
Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma.
- Published
- 2018
9. Investigation of the role and modulation of autophagy for neuroprotection and nerve regeneration using models of peripheral nerve injury
- Author
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Casas Louzao, Catalina, Leiva Rodríguez, Tatiana, Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia, Casas Louzao, Catalina, Leiva Rodríguez, Tatiana, and Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia
- Abstract
Departament responsable de la tesi: Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia., Lesiones en el nervio periférico causan una disrupción axonal que puede producir una neurodegeneración retrograda. Las neuronas axotomizadas sufren una serie de cambios fenotípicos a nivel molecular y celular, algunos de ellos llamados mecanismos endógenos de neuroprotección, que promueven la supervivencia neuronal. En estos mecanismos se incluyen la respuesta de proteína desplegada (UPR) y la autofagia. La intensidad y el tiempo de respuesta de la neurona vienen influenciados por la severidad de la lesión, la distancia respecto al soma, el tipo de neurona y la edad. Sin embargo, cuando la lesión es muy proximal al soma, como es el caso de la lesión de avulsión de raíz de nervio periférico (RA), los mecanismos endógenos de neuroprotección pueden no ser activados contribuyendo a la neurodegeneración. Por este motivo creemos que la corrección o la potenciación de los mecanismos endógenos podrían ser efectivos para la neuroprotección y la regeneración. Primero caracterizamos el estado de flujo autofágico después de PNI in vivo y encontramos un bloqueo de estas vías, alteraciones en proteínas relacionadas con microtúbulos y proteínas de tráfico vesicular a los 5-7 días posteriores a la lesión. Posteriormente, modelamos algunos eventos concomitantes asociados con las alteraciones de la autofagia y en el citoesqueleto en el modelo in vitro. Además, analizamos la respuesta temporal de la autofagia y el citoesqueleto in vitro. Estos resultados, revelaron que la neurodegeneración podría ocurrir debido a la alteración inicial de los microtúbulos después del bloqueo de la autofagia. Además,estas alteraciones del citoesqueleto aumentan la astrogliosis y la muerte de MN in vivo. Finalmente, exploramos el papel de la potenciación de la autofagia. El análisis del curso temporal de la inducción de autofagia farmacológica usando rapamicina reveló ser neuroprotector solo como un pretratamiento antes de la lesión de RA. Además, la activación de la autofagia mediada por la sobreexpresi, Severe peripheral nerve injury (PNI) cause axonal disruption and may produce retrograde neurodegeneration. Axotomized neurons undergo a series of phenotypic changes at the molecular and cellular levels, some of them called endogenous mechanisms of neuroprotection, that promote neuronal survival that includes the unfolded protein response (UPR), the heat-shock response, the autophagy pathway, the ubiquitin-proteasome system, chaperone, the endoplasmic reticulum (ER)-associated degradation machinery (ERAD) and the antioxidant defence. The intensity and time course of the neuronal response are mainly influenced by the severity of the injury, distance of the lesion to cell body, type of neuron and age. However, when the injury is proximal to the soma, such in the case of peripheral nerve root avulsion (RA), the endogenous mechanisms of neuroprotection might not be properly activated contributing to neurodegeneration. We reasoned that the correction or potentiation of these mechanisms might be effective for neuroprotection. We first characterize the state of autophagy flux after PNI in vivo and found a blockage of these pathway, alterations in microtubule related proteins and vesicle trafficking proteins at 5-7 days post-injury Subsequently, we modelize some concomitant events associated with autophagy failure such as cytoskeleton abnormalities in in vitro model. Furthermore, we analyse the time course response of autophagy and cytoskeleton in vitro. These revealed that neurodegeneration might occur due to initial microtubule alteration followed autophagy blockage. These cytoskeleton alterations increase astrogliosis and MN death in vivo. Finally, we explored the role of autophagy potentiation. Time-course analysis of pharmacological autophagy induction using rapamycin revealed to be neuroprotective only as a pre-treatment before RA injury. In addition, autophagy activation mediated by ATG5 overexpression resulted in a MN preservation accompanied by improved internal tra
- Published
- 2019
10. Investigation of the role and modulation of autophagy for neuroprotection and nerve regeneration using models of peripheral nerve injury
- Author
-
Leiva Rodríguez, Tatiana, Casas Louzao, Catalina, and Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia
- Subjects
Lesiones de nervio periférico ,Degeneración ,Autofàgia ,Ciències Experimentals ,Lesions de nervi perifèric ,Peripheral nerve injury ,Degeneració ,Autophagy ,Degeneration ,Autofagia - Abstract
Lesiones en el nervio periférico causan una disrupción axonal que puede producir una neurodegeneración retrograda. Las neuronas axotomizadas sufren una serie de cambios fenotípicos a nivel molecular y celular, algunos de ellos llamados mecanismos endógenos de neuroprotección, que promueven la supervivencia neuronal. En estos mecanismos se incluyen la respuesta de proteína desplegada (UPR) y la autofagia. La intensidad y el tiempo de respuesta de la neurona vienen influenciados por la severidad de la lesión, la distancia respecto al soma, el tipo de neurona y la edad. Sin embargo, cuando la lesión es muy proximal al soma, como es el caso de la lesión de avulsión de raíz de nervio periférico (RA), los mecanismos endógenos de neuroprotección pueden no ser activados contribuyendo a la neurodegeneración. Por este motivo creemos que la corrección o la potenciación de los mecanismos endógenos podrían ser efectivos para la neuroprotección y la regeneración. Primero caracterizamos el estado de flujo autofágico después de PNI in vivo y encontramos un bloqueo de estas vías, alteraciones en proteínas relacionadas con microtúbulos y proteínas de tráfico vesicular a los 5-7 días posteriores a la lesión. Posteriormente, modelamos algunos eventos concomitantes asociados con las alteraciones de la autofagia y en el citoesqueleto en el modelo in vitro. Además, analizamos la respuesta temporal de la autofagia y el citoesqueleto in vitro. Estos resultados, revelaron que la neurodegeneración podría ocurrir debido a la alteración inicial de los microtúbulos después del bloqueo de la autofagia. Además,estas alteraciones del citoesqueleto aumentan la astrogliosis y la muerte de MN in vivo. Finalmente, exploramos el papel de la potenciación de la autofagia. El análisis del curso temporal de la inducción de autofagia farmacológica usando rapamicina reveló ser neuroprotector solo como un pretratamiento antes de la lesión de RA. Además, la activación de la autofagia mediada por la sobreexpresión de ATG5 dio como resultado una preservación de MN acompañada de una mejora en la vía secretora y el flujo autofagico. Resultados previos demostraron que BiP neuroprotegía frente a RA y que su expresión se veía disminuida en las motoneuronas degeneradas. Considerando su relación con la autofagia, nuestro objetivo fue aclarar los mecanismos de neuroprotección mediante la proteómica. Descubrimos que la sobrexpresión de GRP78/BiP promovía la reducción de proteínas mitocondriales mediante la inducción de la mitofagia. Esta activación era dependiente de IP3R y PINK1 Finalmente, considerando que una terapia efectiva después de la lesión de nervio periférico promueve el crecimiento axonal y la regeneración nerviosa, exploramos si la potenciación de la autofagia podría ser pro-regenerativa. Finalmente, considerando que una terapia efectiva después de la PNI debería promover el rebrote axonal y la regeneración nerviosa, exploramos si la estimulación autofagia también podría ser pro-regenerativa. Descubrimos que la autofagia mediada por SIRT-1/ HIF1α promueve el crecimiento de neuritas in vitro. Además, la potenciación de la autofagia mediante la sobrexpresión de ATG5 o SIRT1 acelera la recuperación funcional y el crecimiento axonal después de la lesión. Estos hallazgos sugieren que la corrección o la potenciación de los mecanismos endógenos como la autofagia, pueden ser una terapia eficaz para aumentar la supervivencia de las motoneuronas desconectadas y mejorar el crecimiento axonal después de las lesiones de nervio periférico. Severe peripheral nerve injury (PNI) cause axonal disruption and may produce retrograde neurodegeneration. Axotomized neurons undergo a series of phenotypic changes at the molecular and cellular levels, some of them called endogenous mechanisms of neuroprotection, that promote neuronal survival that includes the unfolded protein response (UPR), the heat-shock response, the autophagy pathway, the ubiquitin-proteasome system, chaperone, the endoplasmic reticulum (ER)-associated degradation machinery (ERAD) and the antioxidant defence. The intensity and time course of the neuronal response are mainly influenced by the severity of the injury, distance of the lesion to cell body, type of neuron and age. However, when the injury is proximal to the soma, such in the case of peripheral nerve root avulsion (RA), the endogenous mechanisms of neuroprotection might not be properly activated contributing to neurodegeneration. We reasoned that the correction or potentiation of these mechanisms might be effective for neuroprotection. We first characterize the state of autophagy flux after PNI in vivo and found a blockage of these pathway, alterations in microtubule related proteins and vesicle trafficking proteins at 5-7 days post-injury Subsequently, we modelize some concomitant events associated with autophagy failure such as cytoskeleton abnormalities in in vitro model. Furthermore, we analyse the time course response of autophagy and cytoskeleton in vitro. These revealed that neurodegeneration might occur due to initial microtubule alteration followed autophagy blockage. These cytoskeleton alterations increase astrogliosis and MN death in vivo. Finally, we explored the role of autophagy potentiation. Time-course analysis of pharmacological autophagy induction using rapamycin revealed to be neuroprotective only as a pre-treatment before RA injury. In addition, autophagy activation mediated by ATG5 overexpression resulted in a MN preservation accompanied by improved internal trafficking and autophagy flux. Previous data demonstrated neuroprotective capacities mediated by GRP78/BiP overexpression that it has been found downregulated in degenerated MNs after the lesion. Considering its relationship with autophagy, we aimed to clarify the mechanisms of these neuroprotection by proteomic analysis. We discovered that GRP78/BiP overexpression induces the downregulation of mitochondrial proteins by the induction of mitophagy. In this activation of mitophagy by GRP78/BiP is implicated IP3R and PINK1 Finally, considering that an effective therapy after PNI should promote axonal regrowth and nerve regeneration, we explored if autophagy stimulation might be pro-regenerative as well. We did so by overexpressing ATG5 or by genetic and pharmacological activation of SIRT1. We discovered that autophagy mediated by SIRT-1/HIF1α promotes neurite outgrowth in vitro. In addition, autophagy potentiation by ATG5 or SIRT1 overexpression enhances functional recovery and axonal growth after the lesion. Overall, these findings suggested that correction or potentiation of endogenous mechanisms such as autophagy may be an effective therapy to increase the survival of disconnected MNs and enhanced axonal regrowth after the peripheral nerve injuries.
- Published
- 2018
11. SIRT1 activation with neuroheal is neuroprotective but SIRT2 inhibition with AK7 is detrimental for disconnected motoneurons
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Romeo Guitart, David, Leiva Rodríguez, Tatiana, Espinosa Alcantud, María, Sima, Núria, Vaquero, Alejandro, Domínguez Martín, Helena, Ruano Caballero, Diego, Casas, Catalina, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Romeo Guitart, David, Leiva Rodríguez, Tatiana, Espinosa Alcantud, María, Sima, Núria, Vaquero, Alejandro, Domínguez Martín, Helena, Ruano Caballero, Diego, and Casas, Catalina
- Abstract
Sirtuin 1 (SIRT1) activity is neuroprotective, and we have recently demonstrated its role in the retrograde degenerative process in motoneurons (MNs) in the spinal cord of rats after peripheral nerve root avulsion (RA) injury. SIRT2 has been suggested to exert effects opposite those of SIRT1; however, its roles in neurodegeneration and neuron response after nerve injury remain unclear. Here we compared the neuroprotective potentials of SIRT1 activation and SIRT2 inhibition in a mouse model of hypoglossal nerve axotomy. This injury induced a reduction of around half MN population within the hypoglossal nucleus by a non-apoptotic neurodegenerative process triggered by endoplasmic reticulum (ER) stress that resulted in activation of the unfolded protein response mediated by IRE1α and XBP1 by 21 days post injury. Both SIRT1 activation with NeuroHeal and SIRT2 inhibition with AK7 protected NSC-34 motor neuron-like cells against ER stress in vitro. In agreement with the in vitro results, NeuroHeal treatment or SIRT1 overexpression was neuroprotective of axotomized hypoglossal MNs in a transgenic mouse model. In contrast, AK7 treatment or SIRT2 genetic depletion in mice inhibited damaged MN survival. To resolve the in vitro/in vivo discrepancies, we used an organotypic spinal cord culture system that preserves glial cells. In this system, AK7 treatment of ER-stressed organotypic cultures was detrimental for MNs and increased microglial nuclear factor-κB and the consequent transcription of cytotoxic pro-inflammatory factors similarly. The results highlight the importance of glial cells in determining the neuroprotective impact of any treatment.
- Published
- 2018
12. Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence
- Author
-
Romeo-Guitart, David, primary, Forés, Joaquim, additional, Herrando-Grabulosa, Mireia, additional, Valls, Raquel, additional, Leiva-Rodríguez, Tatiana, additional, Galea, Elena, additional, González-Pérez, Francisco, additional, Navarro, Xavier, additional, Petegnief, Valerie, additional, Bosch, Assumpció, additional, Coma, Mireia, additional, Mas, José Manuel, additional, and Casas, Caty, additional
- Published
- 2018
- Full Text
- View/download PDF
13. GRP78 Overexpression Triggers PINK1-IP 3 R-Mediated Neuroprotective Mitophagy.
- Author
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Leiva-Rodríguez, Tatiana, Romeo-Guitart, David, Herrando-Grabulosa, Mireia, Muñoz-Guardiola, Pau, Polo, Miriam, Bañuls, Celia, Petegnief, Valerie, Bosch, Assumpció, Lizcano, Jose Miguel, Apostolova, Nadezda, Forés, Joaquim, and Casas, Caty
- Subjects
ENDOPLASMIC reticulum ,NEUROPROTECTIVE agents ,GENETIC engineering ,DRUG design ,CELL physiology - Abstract
An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
14. Neuroprotective drug for nerve trauma revealed using artificial intelligence
- Author
-
Joaquim Forés, Xavier Navarro, Raquel Valls, Francisco González-Pérez, José Manuel Mas, Tatiana Leiva-Rodríguez, David Romeo-Guitart, Valérie Petegnief, Elena Galea, Mireia Herrando-Grabulosa, Assumpció Bosch, Caty Casas, Mireia Coma, Fundació La Marató de TV3, Ministerio de Economía y Competitividad (España), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), European Commission, Romeo-Guitart, David, Leiva-Rodríguez, Tatiana, Navarro, Xavier, Casas, Caty, Romeo-Guitart, David [0000-0003-3368-9302], Leiva-Rodríguez, Tatiana [0000-0003-0359-0045], Navarro, Xavier[0000-0001-9849-902X], and Casas, Caty [0000-0002-2273-6321]
- Subjects
0301 basic medicine ,Nervous system ,Systems biology ,lcsh:Medicine ,Neuroprotection ,Article ,Cell Line ,Machine Learning ,Rats, Sprague-Dawley ,Mice ,03 medical and health sciences ,Neuroprotective drug ,Artificial Intelligence ,medicine ,Animals ,Radiculopathy ,lcsh:Science ,Surgical repair ,Multidisciplinary ,biology ,Drug discovery ,business.industry ,Sirtuin 1 ,lcsh:R ,Peripheral Nervous System Diseases ,Recovery of Function ,Nerve trauma ,Nerve Regeneration ,Rats ,Neuroprotective Agents ,030104 developmental biology ,medicine.anatomical_structure ,Spinal Cord ,biology.protein ,Wounds and Injuries ,Female ,lcsh:Q ,Artificial intelligence ,Spinal Nerve Roots ,business ,Algorithms - Abstract
Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma., This work was mainly supported by a grant from Fundació La Marató-TV3 (#110432, CC, AB & VP) that funded the work and contracts of TLR and MHG and partially by the Ministerio de Economía y Competitividad of Spain (#SAF 2014-59701, CC, DRG, & TLR). We are also grateful for support from CIBERNED and funding from the European Union Seventh Framework Programme for research, technological development, and demonstration (#306240, XN, FRP & CC). Part of the research leading to these results has also received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 306240.
- Published
- 2018
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