RRC ID 45763
Author Juang BT, Ludwig AL, Benedetti KL, Gu C, Collins K, Morales C, Asundi A, Wittmann T, L'Etoile N, Hagerman PJ.
Title Expression of an expanded CGG-repeat RNA in a single pair of primary sensory neurons impairs olfactory adaptation in Caenorhabditis elegans.
Journal Hum. Mol. Genet.
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.
Volume 23(18)
Pages 4945-59
Published 2014-9-15
DOI 10.1093/hmg/ddu210
PII ddu210
PMID 24821701
PMC PMC4140470
MeSH 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
IF 4.544
Times Cited 1
C.elegans tm1489