Reduction of Fmr1 mRNA Levels Rescues Pathological Features in Cortical Neurons in a Model of FXTAS
Reduction of Fmr1 mRNA Levels Rescues Pathological Features in Cortical Neurons in a Model of FXTAS
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DOI：
10.1016/j.omtn.2019.09.018
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发表时间：
2019-12-06
影响因子：
8.8
通讯作者：
Bardoni, Barbara
中科院分区：
文献类型：
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作者：
Drozd, Malgorzata;Delhaye, Sebastien;Bardoni, Barbara
脆性 X 相关震颤共济失调综合征 (FXTAS) 是一种罕见疾病，与脆性 X 前突变的存在相关，即 FMR1 基因 50 UTR 中的 55-200 CGG 重复扩增。 CGG前突变携带者有两种主要的神经表型：（1）以焦虑、注意力缺陷多动障碍（ADHD）、社交缺陷或自闭症谱系障碍（ASD）为特征的神经发育障碍； (2) 50岁后，FXTAS表型。这种神经退行性疾病的特征是共济失调和一种帕金森病。这种疾病的分子病理学特征是存在脆性 X 型精神发育迟滞 1 (FMR1) mRNA 水平升高、存在重复相关的非 AUG (RAN) 翻译肽以及含有 FMR1 mRNA 的核包涵体。虽然过去 FXTAS 主要被认为是一种迟发性疾病，但患者的一些表型以及 FXTAS 小鼠模型学习和记忆行为的改变表明这种疾病涉及神经发育。为了更好地了解 Fmr1 mRNA 水平增加在神经元分化过程中的生理病理学作用，我们使用小干扰 RNA (siRNA) 方法来减少 FXTAS 小鼠模型培养的皮层神经元中该 mRNA 的丰度。这种方法挽救了神经元形态的改变。这种细胞表型与我们通过质谱分析鉴定的差异表达蛋白质相关。有趣的是，表型拯救还与参与各种途径的 29 种蛋白质丰度的拯救有关，这些蛋白质代表了早期治疗方法的假定目标。
Fragile X-associated tremor ataxia syndrome (FXTAS) is a rare disorder associated to the presence of the fragile X premutation, a 55-200 CGG repeat expansion in the 50 UTR of the FMR1 gene. Two main neurological phenotypes have been described in carriers of the CGG premutation: (1) neurodevelopmental disorders characterized by anxiety, attention deficit hyperactivity disorder (ADHD), social deficits, or autism spectrum disorder (ASD); and (2) after 50 years old, the FXTAS phenotype. This neurodegenerative disorder is characterized by ataxia and a form of parkinsonism. The molecular pathology of this disorder is characterized by the presence of elevated levels of Fragile X Mental Retardation 1 (FMR1) mRNA, presence of a repeat-associated non-AUG (RAN) translated peptide, and FMR1 mRNA-containing nuclear inclusions. Whereas in the past FXTAS was mainly considered as a late-onset disorder, some phenotypes of patients and altered learning and memory behavior of a mouse model of FXTAS suggested that this disorder involves neurodevelopment. To better understand the physiopathological role of the increased levels of Fmr1 mRNA during neuronal differentiation, we used a small interfering RNA (siRNA) approach to reduce the abundance of this mRNA in cultured cortical neurons from the FXTAS mouse model. Morphological alterations of neurons were rescued by this approach. This cellular phenotype is associated to differentially expressed proteins that we identified by mass spectrometry analysis. Interestingly, phenotype rescue is also associated to the rescue of the abundance of 29 proteins that are involved in various pathways, which represent putative targets for early therapeutic approaches.