Cis-silencing of PIP5K1B evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies
Autor: | Pierre Rustin, Isabelle Husson, Aurélien Bayot, Sacha Reichman, Sophie Lebon, Zsolt Csaba, Ghislaine Sterkers, Laetitia Aubry, Malgorzata Rak |
---|---|
Rok vydání: | 2013 |
Předmět: |
Phosphatidylinositol 4
5-Diphosphate Ataxia Biology Phosphatidylinositol Phosphates Iron-Binding Proteins Genetics medicine Humans Gene silencing Gene Silencing Lymphocytes Cytoskeleton Molecular Biology Genetics (clinical) Actin Gene knockdown General Medicine Fibroblasts Actin cytoskeleton Molecular biology Phosphotransferases (Alcohol Group Acceptor) Friedreich Ataxia Frataxin biology.protein medicine.symptom Trinucleotide Repeat Expansion Trinucleotide repeat expansion |
Zdroj: | Human Molecular Genetics. 22:2894-2904 |
ISSN: | 1460-2083 0964-6906 |
Popis: | Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease characterized by ataxia, variously associating heart disease, diabetes mellitus and/or glucose intolerance. It results from intronic expansion of GAA triplet repeats at the FXN locus. Homozygous expansions cause silencing of the FXN gene and subsequent decreased expression of the encoded mitochondrial frataxin. Detailed analyses in fibroblasts and neuronal tissues from FRDA patients have revealed profound cytoskeleton anomalies. So far, however, the molecular mechanism underlying these cytoskeleton defects remains unknown. We show here that gene silencing spreads in cis over the PIP5K1B gene in cells from FRDA patients (circulating lymphocytes and primary fibroblasts), correlating with expanded GAA repeat size. PIP5K1B encodes phosphatidylinositol 4-phosphate 5-kinase β type I (pip5k1β), an enzyme functionally linked to actin cytoskeleton dynamics that phosphorylates phosphatidylinositol 4-phosphate [PI(4)P] to generate phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Accordingly, loss of pip5k1β function in FRDA cells was accompanied by decreased PI(4,5)P2 levels and was shown instrumental for destabilization of the actin network and delayed cell spreading. Knockdown of PIP5K1B in control fibroblasts using shRNA reproduced abnormal actin cytoskeleton remodeling, whereas over-expression of PIP5K1B, but not FXN, suppressed this phenotype in FRDA cells. In addition to provide new insights into the consequences of the FXN gene expansion, these findings raise the question whether PIP5K1B silencing may contribute to the variable manifestation of this complex disease. |
Databáze: | OpenAIRE |
Externí odkaz: |