Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.

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 th...

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Autores principales:	Yunting Lin, Chengyuan Tang, Hua He, Ranhui Duan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4dfd52dca8224e3f97f135e2a7943068
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spelling	oai:doaj.org-article:4dfd52dca8224e3f97f135e2a79430682021-11-18T07:48:14ZActivation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.1932-620310.1371/journal.pone.0062572https://doaj.org/article/4dfd52dca8224e3f97f135e2a79430682013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23626835/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Fragile 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.Yunting LinChengyuan TangHua HeRanhui DuanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e62572 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yunting Lin Chengyuan Tang Hua He Ranhui Duan Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.
description	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.
format	article
author	Yunting Lin Chengyuan Tang Hua He Ranhui Duan
author_facet	Yunting Lin Chengyuan Tang Hua He Ranhui Duan
author_sort	Yunting Lin
title	Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.
title_short	Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.
title_full	Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.
title_fullStr	Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.
title_full_unstemmed	Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.
title_sort	activation of mtor ameliorates fragile x premutation rcgg repeat-mediated neurodegeneration.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/4dfd52dca8224e3f97f135e2a7943068
work_keys_str_mv	AT yuntinglin activationofmtoramelioratesfragilexpremutationrcggrepeatmediatedneurodegeneration AT chengyuantang activationofmtoramelioratesfragilexpremutationrcggrepeatmediatedneurodegeneration AT huahe activationofmtoramelioratesfragilexpremutationrcggrepeatmediatedneurodegeneration AT ranhuiduan activationofmtoramelioratesfragilexpremutationrcggrepeatmediatedneurodegeneration
_version_	1718422908721692672

Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.

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