title: rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA.
abstract: T2-family acidic endoribonucleases are represented in all genomes. A physiological role for RNase T2 has yet to be defined for metazoa. RNASET2 mutation in humans is linked with a leukoencephalopathy that arises in infancy characterized by cortical cysts and multifocal white matter lesions. We now show localization of RNASET2 within lysosomes. Further, we demonstrate that loss of rnaset2 in mutant zebrafish results in accumulation of undigested rRNA within lysosomes within neurons of the brain. Further, by using high field intensity magnetic resonance microimaging, we reveal white matter lesions in these animals comparable to those observed in RNASET2-deficient infants. This correlates with accumulation of Amyloid precursor protein and astrocytes at sites of neurodegeneration. Thus we conclude that familial cystic leukoencephalopathy is a lysosomal storage disorder in which rRNA is the best candidate for the noxious storage material.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Noémie
authors.initials: N
authors.lastname: Haud
authors.forename: Firat
authors.initials: F
authors.lastname: Kara
authors.forename: Simone
authors.initials: S
authors.lastname: Diekmann
authors.forename: Marco
authors.initials: M
authors.lastname: Henneke
authors.forename: Jason R
authors.initials: JR
authors.lastname: Willer
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Hillwig
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Macintosh
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.forename: A
authors.initials: A
authors.lastname: Alia
authors.forename: Adam F L
authors.initials: AF
authors.lastname: Hurlstone
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D017403:In Situ Hybridization; D056784:Leukoencephalopathies / Q000235:genetics*; D016464:Lysosomal Storage Diseases / Q000235:genetics*; D008247:Lysosomes / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020871:RNA Stability / Q000235:genetics / Q000502:physiology*; D012335:RNA, Ribosomal / Q000378:metabolism*; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics*
chemical_list: D012335:RNA, Ribosomal; D025521:Tumor Suppressor Proteins; D012260:Ribonucleases; C425232:RNASET2 protein, human