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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy / drug effects
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Autophagy / genetics
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Disease Models, Animal
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Drosophila
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Enzyme Activation / drug effects
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Fragile X Mental Retardation Protein / genetics*
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Fragile X Syndrome / genetics*
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Fragile X Syndrome / metabolism*
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Humans
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism
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Phenotype
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / metabolism*
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Trinucleotide Repeat Expansion*
Substances
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FMR1 protein, human
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Fragile X Mental Retardation Protein
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TOR Serine-Threonine Kinases
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Sirolimus
Grants and funding
This work was supported in part by National Natural Science Foundation of China (grant number: 81071028, 81172513), Program for New Century Excellent Talents (grant number: 7603230006), the Major State Basic Research Development Program of China (973 Program) (grant number: 2011CB510000, 2012CB944600) and the Graduate degree thesis Innovation Foundation of Central South University (grant number: 2011ssxt255). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.