Browsing by Author "Colombo, Alicia"

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    ALS-linked protein disulfide isomerase variants cause motor dysfunction
    (European Molecular Biology Organization by IRL Press, 2016) Woehlbier, Ute; Colombo, Alicia; Saaranen, Mirva; Pérez, Viviana; Ojeda, Jorge; Bustos, Fernando; Andreu, Catherine; Torres, mauricio; Valenzuela, Vicente; Medinas, Danilo; Rozas, Pablo; Vidal, René; López-González, Rodrigo; Salameh, Johnny; Fernández-Collemann, Sara; Muñoz, Natalia; Matus, Soledad; Armisén, Ricardo; Sagredo, Alfredo; Palma, Karina; Irrazabal, Thergiory; Almeida, Sandra; González-Pérez, Paloma; Campero, Mario
    Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.
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    Validation of an NGS Panel Designed for Detection of Actionable Mutations in Tumors Common in Latin America
    (2021) Salvo, Mauricio; González‐Feliú, Evelin; Toro, Jessica; Gallegos, Iván; Maureira, Ignacio; Miranda‐González, Nicolás; Barajas, Olga; Bustamante, Eva; Ahumada, Mónica; Colombo, Alicia; Armisén, Ricardo; Villamán, Camilo; Ibáñez, Carolina; Bravo, María Loreto; Sanhueza, Verónica; Spencer, M. Loreto; Toro, Gonzalo de; Morales, Erik; Bizama, Carolina; García, Patricia; Carrasco, Ana María; Gutiérrez, Lorena; Bermejo, Justo Lorenzo; Verdugo, Ricardo A.; Marcelain, Katherine
    Next‐generation sequencing (NGS) is progressively being used in clinical practice. How‐ ever, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25‐gene panel that contains pre‐ dictive biomarkers for most current and near‐future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin‐fixed paraffin‐embedded tissue. The workflow includes an automated bioinformatic pipeline that ac‐ counts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were de‐ tected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost‐efficient alternative to multiple non‐NGS assays and costly, large NGS panels. This kind of streamlined assay with au‐ tomated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.

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