Fragile X syndrome (FXS) carriers have FMR1 alleles, called premutations, with an intermediate number of 5'-untranslated CGG-repeats between patients (>200 repeats) and normal individuals (<60 repeats). Fragile X-associated tremor/ataxia syndrome (FXTAS), a late age of onset neurodegenerative disorder, has been recognized in older males of fragile X premutation carriers, which is uncoupled from the neurodevelopmental disorder, FXS. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS. Several lines of evidence, including ours, have led to the proposal of an RNA (fragile X premutation rCGG repeats)-mediated gain-of-function toxicity model for FXTAS, in which rCGG repeat-binding proteins (RBPs) could become functionally limited by their sequestration to lengthy rCGG repeats. We have identified two known RNA-binding proteins, Pur 1 and hnRNP A2/B1, as RBPs. Both Pur 1 and the heterodimer complex, hnRNP A2/CUGBP1, could modulate the rCGG-mediated toxicity in Drosophila model, supporting RNA-mediated sequestration model of FXTAS. In this proposal, we will use both Drosophila and mouse models to further test the hypothesis that FXTAS results from abnormal RNA metabolism that stems from inappropriate association of RBPs with the RNA produced by FMR1 premutation alleles.
Four aims are proposed: 1) To determine whether Pur 1 and hnRNP A2/CUGBP1 complex could modulate rCGG-mediated neurodegeneration in mice;2) To determine the role(s) of Cdk5 in rCGG-mediated neurodegeneration;3) To identify the target RNAs of RBPs that are critical for the pathogenesis of FXTAS;4) To Identify novel suppressors and enhancers of rCGG-mediated neurodegeneration. Successful completion of these studies should significantly advance our understanding the molecular pathogenesis of FXTAS. Identifications of genes and pathways involved in FXTAS will provide valuable targets for future pharmacological research aimed at developing drugs for therapy.
Fragile X-associated tremor/ataxia syndrome (FXTAS), a late age of onset neurodegenerative disorder, is mainly associated with older males of fragile X premutation carriers. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS. Here we will use both Drosophila and mouse models to further test the hypothesis that FXTAS results from abnormal RNA metabolism that stems from inappropriate association of RBPs with the RNA produced by FMR1 premutation alleles.
|Oh, Yohan; Zhang, Feiran; Wang, Yaqing et al. (2017) Zika virus directly infects peripheral neurons and induces cell death. Nat Neurosci 20:1209-1212|
|Yang, Su; Chang, Renbao; Yang, Huiming et al. (2017) CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease. J Clin Invest 127:2719-2724|
|Yoon, Ki-Jun; Ringeling, Francisca Rojas; Vissers, Caroline et al. (2017) Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell 171:877-889.e17|
|Yoon, Ki-Jun; Song, Guang; Qian, Xuyu et al. (2017) Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins. Cell Stem Cell 21:349-358.e6|
|Li, Liping; Zang, Liqun; Zhang, Feiran et al. (2017) Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 26:2398-2411|
|Kong, Ha Eun; Zhao, Juan; Xu, Shunliang et al. (2017) Fragile X-Associated Tremor/Ataxia Syndrome: From Molecular Pathogenesis to Development of Therapeutics. Front Cell Neurosci 11:128|
|Li, Xuekun; Yao, Bing; Chen, Li et al. (2017) Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis. Nat Commun 8:15903|
|Yao, Bing; Cheng, Ying; Wang, Zhiqin et al. (2017) DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress. Nat Commun 8:1122|
|Nott, Alexi; Cheng, Jemmie; Gao, Fan et al. (2016) Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat Neurosci 19:1497-1505|
|Wang, Zhiqin; Tang, Beisha; He, Yuquan et al. (2016) DNA methylation dynamics in neurogenesis. Epigenomics 8:401-14|
Showing the most recent 10 out of 69 publications