Examinando por Autor "Colombo, Alicia"
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Ítem ALS-linked protein disulfide isomerase variants cause motor dysfunction(EMBO Journal. Volume 35, Issue 8, Pages 845 - 865. 15 April 2016, 2016-04) Woehlbier, Ute; Colombo, Alicia; Saaranen, Mirva J; Pérez, Viviana; Ojeda, Jorge; Bustos, Fernando J.; Andreu, Catherine I.; Torres, Mauricio; Valenzuela, Vicente; Medinas, Danilo B; Rozas, Pablo; Vidal, Rene L.; Lopez-Gonzalez, Rodrigo; Salameh, Johnny; Fernandez-Collemann, Sara; Muñoz, Natalia; Matus, Soledad; Armisen, Ricardo; Sagredo, Alfredo; Palma, Karina; Irrazabal, Thergiory; Almeida, Sandra; Gonzalez-Perez, Paloma; Campero, Mario; Gao, Fen-Biao; Henny, Pablo; Van Zundert, Brigitte; Ruddock, Lloyd W; Concha, Miguel L; Henriquez, Juan P.; Brown, Robert H.; Hetz, ClaudioDisturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.Ítem Efecto de la mutación de la enzima 3-hidroxi-3-metilglutaril coenzima a reductaza 1B en el desarrollo cráneo-facial de pez cebra (Danio rerio)(Universidad Andrés Bello, 2012) Ávalos E., Allison; Cortés A., Karol; Colombo, Alicia; Facultad de Ciencias de la Salud; Escuela de Tecnología MédicaEn este proyecto analizaremos los cambios inducidos por defectos en la biosíntesis del colesterol e isoprenoides en el desarrollo cráneo-facial de pez cebra. Para este propósito, utilizaremos embriones mutantes (hmgcrlbs 617-/- ) para el gen 3-hidroxi-3-metilglutaril coenzima A reductasa 1 b (hmgcrl b), que codifica para la enzima HMGCRl b (1 0). Esta enzima está bajo un estricto control dentro de la ruta de la síntesis de colesterol e isoprenoides (1 1). Con el fin de detectar sí la ausencia de la función de la enzima HMGCRlb, induce efectos en el desarrollo orofacial, realizamos tinción con azul de Alcián, la que nos permitió observar directamente el tejido cartilaginoso cráneo-facial (12), de tal manera que se pudo evidenciar alteraciones fenotipicas orofaciales en larvas mutantes para hmgcrlb. Posteriormente, realizamos hibridación in situ para determinar si existen cambios en el patrón de expresión de los genes: distal-less homeobox 2 alpha (dlx2a) y collagen type II, alpha 1 (col2al), factores genéticos importantes que modulan algunos eventos tempranos y tardíos de la morfogénesis cráneo-facial, respectivamente (1 0,13).Ítem TRPM4 is a novel component of the adhesome required for focal adhesion disassembly, migration and contractility(Public Library of Science, 2015-06) Cáceres, Mónica; Ortiz, Liliana; Recabarren, Tatiana; Romero, Anibal; Colombo, Alicia; Leiva-Salcedo, Elías; Varela, Diego; Rivas, José; Silva, Ian; Morales, Diego; Campusano, Camilo; Almarza, Oscar; Simon, Felipe; Toledo, Hector; Park, Kang-Sik; Trimmer, James S.; Cerda, OscarCellular migration and contractility are fundamental processes that are regulated by a variety of concerted mechanisms such as cytoskeleton rearrangements, focal adhesion turnover, and Ca2+ oscillations. TRPM4 is a Ca2+-activated non-selective cationic channel (Ca2+-NSCC) that conducts monovalent but not divalent cations. Here, we used a mass spectrometry-based proteomics approach to identify putative TRPM4-associated proteins. Interestingly, the largest group of these proteins has actin cytoskeleton-related functions, and among these nine are specifically annotated as focal adhesion-related proteins. Consistent with these results, we found that TRPM4 localizes to focal adhesions in cells from different cellular lineages. We show that suppression of TRPM4 in MEFs impacts turnover of focal adhesions, serum-induced Ca2+ influx, focal adhesion kinase (FAK) and Rac activities, and results in reduced cellular spreading, migration and contractile behavior. Finally, we demonstrate that the inhibition of TRPM4 activity alters cellular contractility in vivo, affecting cutaneous wound healing. Together, these findings provide the first evidence, to our knowledge, for a TRP channel specifically localized to focal adhesions, where it performs a central role in modulating cellular migration and contractility. © 2015, Public Library of Science. All rights reserved. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.