title: Expression of an expanded CGG-repeat RNA in a single pair of primary sensory neurons impairs olfactory adaptation in Caenorhabditis elegans.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe neurodegenerative disorder that affects carriers of premutation CGG-repeat expansion alleles of the fragile X mental retardation 1 (FMR1) gene; current evidence supports a causal role of the expanded CGG repeat within the FMR1 mRNA in the pathogenesis of FXTAS. Though the mRNA has been observed to induce cellular toxicity in FXTAS, the mechanisms are unclear. One common neurophysiological characteristic of FXTAS patients is their inability to properly attenuate their response to an auditory stimulus upon receipt of a small pre-stimulus. Therefore, to gain genetic and cell biological insight into FXTAS, we examined the effect of expanded CGG repeats on the plasticity of the olfactory response of the genetically tractable nematode, Caenorhabditis elegans (C. elegans). While C. elegans is innately attracted to odors, this response can be downregulated if the odor is paired with starvation. We found that expressing expanded CGG repeats in olfactory neurons interfered with this plasticity without affecting either the innate odor-seeking response or the olfactory neuronal morphology. Interrogation of three RNA regulatory pathways indicated that the expanded CGG repeats act via the C. elegans microRNA (miRNA)-specific Argonaute ALG-2 to diminish olfactory plasticity. This observation suggests that the miRNA-Argonaute pathway may play a pathogenic role in subverting neuronal function in FXTAS.
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan.
authors.forename: Bi-Tzen
authors.initials: BT
authors.lastname: Juang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, CA 95616, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Ludwig
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Benedetti
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Collins
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Morales
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Aarati
authors.initials: A
authors.lastname: Asundi
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wittmann
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA pjhagerman@ucdavis.edu noelle.letoile@ucsf.edu.
authors.forename: Noelle
authors.initials: N
authors.lastname: L'Etoile
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, CA 95616, USA, MIND Institute, University of California, Davis, Health System, Sacramento, CA 95817, USA pjhagerman@ucdavis.edu noelle.letoile@ucsf.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D060565:Argonaute Proteins / Q000235:genetics; D001259:Ataxia / Q000235:genetics / Q000473:pathology; D002074:Butanones / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology; D006801:Humans; D009473:Neuronal Plasticity; D018034:Olfactory Receptor Neurons / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D012903:Smell; D014202:Tremor / Q000235:genetics / Q000473:pathology; D019680:Trinucleotide Repeat Expansion
chemical_list: D060565:Argonaute Proteins; D002074:Butanones; D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human