title: Cis-silencing of PIP5K1B evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies.
abstract: 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.
authors.affiliation: Hôpital Robert Debré, INSERM UMR 676 Faculté de Médecine Denis Diderot, Université Paris 7, 75019 Paris, France. aurelien.bayot@inserm.fr
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bayot
authors.forename: Sacha
authors.initials: S
authors.lastname: Reichman
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Csaba
authors.forename: Laetitia
authors.initials: L
authors.lastname: Aubry
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Sterkers
authors.forename: Isabelle
authors.initials: I
authors.lastname: Husson
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rak
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005621:Friedreich Ataxia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); D000096923:Frataxin; C037178:phosphatidylinositol 4-phosphate; C020077:1-phosphatidylinositol-4-phosphate 5-kinase