Identification of p38 MAPK as a novel therapeutic target for Friedreich’s ataxia
Autor: | Eric Ruff, Shujuan Xia, Avinash Kaur, John W. Tobias, Robert B. Wilson, Daniel Lin, M. Grazia Cotticelli, Yongping Wang |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Ataxia Pyridines Cell Primary Cell Culture Clone (cell biology) lcsh:Medicine Mitochondrion Article Small hairpin RNA Mitogen-Activated Protein Kinase 14 03 medical and health sciences 0302 clinical medicine Iron-Binding Proteins medicine Humans Enzyme Inhibitors Phosphorylation RNA Small Interfering lcsh:Science Cells Cultured Multidisciplinary biology Chemistry Gene Expression Profiling lcsh:R Imidazoles Computational Biology Fibroblasts 030104 developmental biology medicine.anatomical_structure Friedreich Ataxia Gene Knockdown Techniques Frataxin biology.protein Cancer research Cytokine secretion lcsh:Q medicine.symptom 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018) Scientific Reports |
ISSN: | 2045-2322 |
Popis: | Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder caused by decreased expression of frataxin, a protein that localizes to mitochondria and is critical for iron-sulfur-cluster (ISC) assembly. There are no proven effective treatments for FRDA. We previously screened a random shRNA library and identified a synthetic shRNA (gFA11) that reverses the growth defect of FRDA cells in culture. We now report that gFA11 decreases cytokine secretion in primary FRDA fibroblasts and reverts other changes associated with cell senescence. The gene-expression profile induced by gFA11 is remarkably similar to the gene-expression profile induced by the p38 MAPK inhibitor SB203580. We found that p38 phosphorylation, indicating activation of the p38 pathway, is higher in FRDA cells than in normal control cells, and that siRNA knockdown of frataxin in normal fibroblasts also increases p38 phosphorylation. Treatment of FRDA cells with p38 inhibitors recapitulates the reversal of the slow-growth phenotype induced by clone gFA11. These data highlight the involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA. |
Databáze: | OpenAIRE |
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