Expression of an Expanded CGG-repeat RNA in a Single Pair of Primary Sensory Neurons Impairs Olfactory Adaptation in Caenorhabditis Elegans

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2014 May 14

PMID 24821701

Citations 5

Authors

Bi-Tzen Juang

Anna L Ludwig

Kelli L Benedetti

Chen Gu

Kimberly Collins

Christopher Morales

Aarati Asundi

Torsten Wittmann

Noelle LEtoile

Paul J Hagerman

Affiliations

Soon will be listed here.

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.

Citing Articles

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on Premutation.

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Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions.

Zhou Z, Jankovic J, Ashizawa T, Tan E Nat Rev Neurol. 2022; 18(3):145-157.

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Non-coding RNA in Fragile X Syndrome and Converging Mechanisms Shared by Related Disorders.

Zhou Y, Hu Y, Sun Q, Xie N Front Genet. 2019; 10:139.

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Models and mechanisms of repeat expansion disorders: a worm's eye view.

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Fragile X-associated tremor/ataxia syndrome.

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