TUNEL positive cells were counted and quantified as described

s modifiers. Data show mean phenotype score 6 SEM. doi:10.1371/journal.pone.0062572.g003 were used to verify the expression levels of S6K and 4E-BP1. Based on these results, we concluded that activation of mTOR signaling could repress neurodegenerative phenotypes of FXTAS. Discussion Rapamycin, a neutral 2449244 macrolide with immunosuppressive properties, has been proven to extend lifespan and to have 10725256 a protective effect in many neurodegenerative diseases through induction of autophagy. As rapamycin protects against neuron death, alleviates neurotoxicity, and reduces the formation of aggregates in experimental models of other neurodegenerative disorders, we expected to see similar protective effects in FXTAS. Unfortunately, rapamycin did not ameliorate the neurodegenerative phenotypes of FXTAS in our Drosophila model instead aggravating them. Recognized as an arbiter of neuronal survival and death decisions in many neurodegenerative diseases, autophagy is the most crucial cellular process involved in the clearance of redundant proteins and components. Activation of autophagy has been demonstrated to mitigate neurotoxicity by promoting degradation of mutant proteins. Nevertheless, intriguingly, we have shown that autophagy alone has no effect on altering neurodegenerative phenotypes of FXTAS. In a previous study by Todd PK, overexpression of histone deacetylase 6 had been shown to suppress CGG90 induced rough eye. Knockdown of autophagy by Atg12 RNAi had no effect on suppression of neurodegeneration by HDAC6, suggesting HDAC6 exerted protective effects by an autophagy-independent mechanism, which fits well with our findings. In most neurodegenerative diseases, which are triggered by formation of aggregates, rapamycin or autophagy is sufficient to decrease the accumulation of mutant proteins and improve neurodegenerative phenotypes. Unlike other neurodegenerative disorders, rapamycin treatment enhanced neurodegeneration in FXTAS and activation of autophagy alone also proved to be ineffective at protecting against degeneration. These findings imply that FXTAS does not share the general pathogenic mechanism that aggregations of mutant proteins cause progressive neuronal dysfunction and loss. Therefore, we speculate that FXTAS, caused by elevated levels of mRNA, possesses unique aspects compared with other neurodegenerative diseases. It’s prerequisite to distinguish FXTAS from other neurodegenerative diseases with the similar symptoms clearly in the diagnostic procedure, especially other ataxia disorders. Importantly, treatment of those patients should be cautious unless accurately diagnosed as rapamycin, or its analogues, may possibly bring about an effect opposite to the one intended. Overexpression of fragile X premutation-length CGG repeats in mice or Drosophila could lead to pathological 169939-93-9 supplier changes similar to patients, including FXTAS and fragile X-associated primary ovarian insufficiency . In FXPOI mice model, significant reductions of phosphorylated AKT and mTOR were observed in ovaries. Our findings definitely suggest that activating AKT/mTOR pathway can improve symptoms of FXTAS. Since both FXTAS and FXPOI result from toxicity of rCGG repeats, we reason that FXTAS and FXPOI share similar therapeutic intervention mechanisms and that, to some extent, the development of mTOR activators will be beneficial to them. In FXTAS patients, the neuropathological hallmark is the presence of eosinophilic and ubiquitin-positive intranuclear inclusions, in b

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