Expression of an expanded CGG-repeat RNA in a single pair of primary sensory neurons impairs olfactory adaptation in Caenorhabditis elegans

Bi-Tzen Juang, Anna L. Ludwig, Kelli L. Benedetti, Chen Gu, Kimberly Collins, Christopher Morales, Aarati Asundi, Torsten Wittmann, Noelle L'Etoile*, Paul J. Hagerman

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish
Article numberddu210
Pages (from-to)4945-4959
Number of pages15
JournalHuman Molecular Genetics
Volume23
Issue number18
DOIs
StatePublished - 1 Jan 2014

Fingerprint Dive into the research topics of 'Expression of an expanded CGG-repeat RNA in a single pair of primary sensory neurons impairs olfactory adaptation in Caenorhabditis elegans'. Together they form a unique fingerprint.

  • Cite this

    Juang, B-T., Ludwig, A. L., Benedetti, K. L., Gu, C., Collins, K., Morales, C., Asundi, A., Wittmann, T., L'Etoile, N., & Hagerman, P. J. (2014). Expression of an expanded CGG-repeat RNA in a single pair of primary sensory neurons impairs olfactory adaptation in Caenorhabditis elegans. Human Molecular Genetics, 23(18), 4945-4959. [ddu210]. https://doi.org/10.1093/hmg/ddu210