title: CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.
abstract: Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5' UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat-associated non-AUG-initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models, and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed by eliminating RAN translation and enhanced by increased polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders in which RAN translation occurs and provide evidence that RAN translation contributes to neurodegeneration.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. petertod@umich.edu
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
authors.forename: Seok Yoon
authors.initials: SY
authors.lastname: Oh
authors.forename: Amy
authors.initials: A
authors.lastname: Krans
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.forename: Michelle
authors.initials: M
authors.lastname: Frazer
authors.forename: Abigail J
authors.initials: AJ
authors.lastname: Renoux
authors.forename: Kai-chun
authors.initials: KC
authors.lastname: Chen
authors.forename: K Matthew
authors.initials: KM
authors.lastname: Scaglione
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.forename: Kojo
authors.initials: K
authors.lastname: Elenitoba-Johnson
authors.forename: Jean P
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Elan D
authors.initials: ED
authors.lastname: Louis
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sutton
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Mills
authors.forename: Nicholas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004330:Drosophila; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis; D014202:Tremor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1