title: RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome.
abstract: Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5' UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via repeat-associated non-AUG (RAN)-initiated translation. Pathologically, FXTAS is characterized by ubiquitin-positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila- and cell-based models of CGG-repeat-associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat-induced degeneration, whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG repeat expression triggered accumulation of a UPS reporter in a length-dependent fashion. To delineate the contributions from CGG repeats as RNA from RAN translation-associated toxicity, we enhanced or impaired the production of FMRpolyG in these models. Driving expression of FMRpolyG enhanced induction of UPS impairment in cell models, while prevention of RAN translation attenuated UPS impairment in cells and suppressed the genetic interaction with UPS manipulation in Drosophila. Taken together, these findings suggest that CGG repeats induce UPS impairment at least in part through activation of RAN translation.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Seok Yoon
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Krans
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Frazer
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA and.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA, Neurology, U.S. Department of Veterans Affairs Medical Center, Ann Arbor, MI, USA petertod@umich.edu.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001259:Ataxia / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D019636:Neurodegenerative Diseases; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D014202:Tremor / Q000235:genetics* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; C467328:FMR1 protein, Drosophila; C497683:FMR1 protein, human