title: Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.
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.
authors.affiliation: The State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan, China.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Lin
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Tang
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.forename: Ranhui
authors.initials: R
authors.lastname: Duan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004330:Drosophila; D004789:Enzyme Activation / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C497683:FMR1 protein, human