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Your search keyword '"Gallego-Flores, Tatiana"' showing total 2 results
Start Over Author "Gallego-Flores, Tatiana" Topic neurodegeneration
2 results on '"Gallego-Flores, Tatiana"'

1. RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1.

Author

Park, Jeehye, Al-Ramahi, Ismael, Tan, Qiumin, Mollema, Nissa, Diaz-Garcia, Javier R., Gallego-Flores, Tatiana, Lu, Hsiang-Chih, Lagalwar, Sarita, Duvick, Lisa, Kang, Hyojin, Lee, Yoontae, Jafar-Nejad, Paymaan, Sayegh, Layal S., Richman, Ronald, Liu, Xiuyun, Gao, Yan, Shaw, Chad A., Arthur, J. Simon C., Orr, Harry T., and Westbrook, Thomas F.

Subjects
MITOGEN-activated protein kinases, ATAXIN, TOXICITY testing, ALZHEIMER'S disease, NEURODEGENERATION, PHARMACOLOGY
Abstract

Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Published
2013
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2. High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration

Author

Ivana Peluso, Boxun Lu, James Palacino, Zhandong Liu, Benjamin A. Bleiberg, Nazish T. Malik, Diego L. Medina, Tatiana Gallego-Flores, George Fan, Kelly C. Erikson, Maria de Haro, Kaifang Pang, Matthew Avalos, Simone Di Paola, Juan Botas, Ismael Al-Ramahi, Javier R. Diaz-Garcia, Marc Hild, Andrew Laitman, Laura Elizabeth Rivers, Al-Ramahi, Ismael, Boxun, Lu, Di Paola Simone, Pang, Kaifang, de Haro Maria, Peluso, Ivana, Gallego-Flores, Tatiana, Malik Nazish, T., Erikson, Kelly, Bleiberg Benjamin, A., Avalos, Matthew, Fan, George, Rivers Laura Elizabeth, Laitman Andrew, M., Diaz-García Javier, R., Hild, Marc, Palacino, Jame, Liu, Zhandong, Medina, D, and Botas, Juan

Subjects
0301 basic medicine, Male, Histology, Huntingtin, Induced Pluripotent Stem Cells, Biology, Article, Pathology and Forensic Medicine, Cell Line, Pathogenesis, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Drosophila Proteins, Humans, Gene, Calcium signaling, Gene knockdown, Gene Expression Profiling, Neurodegeneration, Brain, Cell Biology, Fibroblasts, medicine.disease, Actin cytoskeleton, Cell biology, High-Throughput Screening Assays, Disease Models, Animal, 030104 developmental biology, Drosophila melanogaster, Huntington Disease, Female, 030217 neurology & neurosurgery
Abstract

Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington’s Disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice, and then replicated and/ or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroauthophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.

Published
2018

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