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,Torsten Wittmann,Chen Gu,Kimberly Collins,Paul J Hagerman,Christopher Morales,Noelle L'Etoile,Kelli L Benedetti,Aarati Asundi

doi:10.1093/hmg/ddu210

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.

Highlights

The molecular pathogenesis of the fragile X family of disorders involves expansions of a non-coding CGG-repeat microsatellite in the 5′ untranslated region (5′UTR) of the fragile X mental retardation 1 (FMR1) gene (1 – 4)
fragile X-associated tremor/ataxia syndrome (FXTAS) is a human, progressive neurodegenerative disorder in which the abnormal CGG expansion within the 5′UTR of the FMR1 gene is thought to be the source of abnormal cell function
We report a C. elegans model for premutation-driven dysfunction, and demonstrate that 99 CGG repeats in the 5′UTR of a green fluorescent protein (GFP) reporter lead to defects in neuronal plasticity when expressed solely in an olfactory neuron

Summary

Introduction

The molecular pathogenesis of the fragile X family of disorders involves expansions of a non-coding CGG-repeat microsatellite in the 5′ untranslated region (5′UTR) of the fragile X mental retardation 1 (FMR1) gene (1 – 4). Fragile X syndrome, the most common heritable form of intellectual disability and most common single-gene form of autism, is associated with CGG-repeat expansions that exceed 200 repeats (full mutation), almost always accompanied by epigenetic silencing [5]. Repeat expansions in the 55– 200 range (premutation) give rise to the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS) [6,7,8], and to the reproductive disorder, fragile X-associated primary ovarian insufficiency [9,10]. The repeat is associated with early onset attention and intellectual deficit disorders [2,11].

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