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

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 t...

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Bibliographic Details
Published in:Human molecular genetics 2014-09, Vol.23 (18), p.4945-4959
Main Authors: Juang, Bi-Tzen, Ludwig, Anna L, Benedetti, Kelli L, Gu, Chen, Collins, Kimberly, Morales, Christopher, Asundi, Aarati, Wittmann, Torsten, L'Etoile, Noelle, Hagerman, Paul J
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified
Argonaute Proteins - genetics
Ataxia - genetics
Ataxia - pathology
Butanones - pharmacology
Caenorhabditis elegans - genetics
Caenorhabditis elegans - physiology
Disease Models, Animal
Fragile X Mental Retardation Protein - genetics
Fragile X Syndrome - genetics
Fragile X Syndrome - pathology
Humans
Neuronal Plasticity
Olfactory Receptor Neurons - metabolism
Sensory Receptor Cells - metabolism
Smell
Tremor - genetics
Tremor - pathology
Trinucleotide Repeat Expansion
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddu210