Activation of mTOR Ameliorates Fragile X Premutation rCGG Repeat-Mediated Neurodegeneration

Yunting Lin,Chengyuan Tang,Ranhui Duan,Hua He,Mathias Toft

doi:10.1371/journal.pone.0062572

Yunting Lin, Chengyuan Tang + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0062572

Copy DOI

Journal: PloS one	Publication Date: Apr 23, 2013
Citations: 19	License type: CC BY 4.0

Affiliation: Central South University

Abstract

Fragile X associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder caused by aberrant expansion of CGG repeats in 5′ UTR of FMR1 gene. The elevated mRNA confers a toxic gain-of-function thought to be the critical event of pathogenesis. Expressing rCGG90 repeats of the human FMR1 5′UTR in Drosophila is sufficient to induce neurodegeneration. Rapamycin has been demonstrated to attenuate neurotoxicity by inducing autophagy in various animal models of neurodegenerative diseases. Surprisingly, we observed rapamycin exacerbated rCGG90-induced neurodegenerative phenotypes through an autophagy-independent mechanism. CGG90 expression levels of FXTAS flies exposed to rapamycin presented no significant differences. We further demonstrated that activation of the mammalian target of rapamycin (mTOR) signaling could suppress neurodegeneration of FXTAS. These findings indicate that rapamycin will exacerbate neurodegeneration, and that enhancing autophagy is insufficient to alleviate neurotoxicity in FXTAS. Moreover, these results suggest mTOR and its downstream molecules as new therapeutic targets for FXTAS by showing significant protection against neurodegeneration.

Highlights

Fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by aberrant expansion of CGG repeats in 59 UTR of FMR1 gene
Rapamycin cannot ameliorate but aggravates the neurodegenerative phenotypes in FXTAS Drosophila model To determine if FXTAS shares similar pharmaceutical or genetic modifiers with other neurodegenerative disorders, we used an established Drosophila model of rCGG repeat induced neurodegeneration
Since rapamycin had been generally thought to be the specific inhibitor of mammalian target of rapamycin (mTOR) and autophagy had been proven ineffective at altering neurodegeneration in FXTAS, here we examined the activity of mTOR pathway in FXTAS Drosophila model

Summary

Introduction

Fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by aberrant expansion of CGG repeats in 59 UTR of FMR1 gene. The major clinical features of FXTAS are progressive intention tremor and/or ataxia accompanied by gradual behavioral deficits and cognitive decline [1,2]. An FXTAS Drosophila model that ectopically expresses rCGG90 repeats of the human FMR1 59UTR presents a series of neurodegenerative phenotypes which could imitate clinical features of FXTAS patients [4]. CGG KI mice have shown many important aspects of FXTAS, including elevated mRNA levels, presence of intranuclear inclusions, and progressed cognitive and behavioral declines [5,6,7]. Neurotoxicity in FXTAS Drosophila and mice models reveal a highly significant association with the length and dosage of CGG tracts, and a stronger expression of rCGG90 has more severe consequences [4,8]

Methods

Results

Conclusion