Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects the carriers of premutation alleles (55?200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Common features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline. The neuropathological hallmarks of FXTAS include ubiquitin-positive intranuclear inclusions throughout brain and marked dropout of Purkinje neurons in cerebellum. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS and develop effective therapeutic interventions for FXTAS. At the molecular level, FMR1 CGG premutation carriers exhibit a 2 to 8-fold increase in FMR1 mRNA compared to control individuals. Expression of mutant mRNAs containing long (~100) CGG triplets has been shown to be toxic in cell and animal models. Currently, data support two non-mutually exclusive molecular pathogenesis mechanisms for FXTAS: 1) RNA gain-of-function, in which rCGG repeat-binding proteins (RBPs) become functionally limited through sequestration by lengthy rCGG repeats, and 2) Repeat- associated non-AUG (RAN) translation, whereby translation through the CGG (or antisense CCG) repeats leads to the production of toxic homo-polypeptides, such as FMRpolyG, which in turn interfere with a variety of cellular functions. Our previous work has identified two known RNA-binding proteins, Pur ? and hnRNP A2/B1, as RBPs affected by expression of rCGG. We showed that increased expression of either protein could modulate rCGG-mediated toxicity, supporting the RNA-mediated sequestration model of FXTAS. To determine the contributions of both mechanisms to FXTAS pathogenesis, we have generated transgenic lines of mice that express hnRNP A2/B1 and suppress rCGG repeat-mediated toxicity. In parallel, we have taken both whole genome sequencing and global metabolic profiling approaches combined with fly genetic screens to identify potential additional genetic modifiers of FXTAS. We have found that PSMB5 and the sphingolipid metabolic pathway could modulate rCGG repeat toxicity. In this proposal, we plan to further test the hypothesis that FXTAS results from abnormal RNA metabolism stemming from inappropriate association of RBPs with the RNA produced by FMR1 premutation alleles, as well as determine whether these additional candidate modifiers can modulate FXTAS pathogenesis. 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.

Public Health Relevance

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects the carriers of premutation alleles (55?200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS and develop effective therapeutic interventions for FXTAS. Here we will use both Drosophila and mouse models to test the hypothesis that FXTAS results from abnormal RNA metabolism stemming from inappropriate association of RNA binding proteins with the RNA produced by FMR1 premutation alleles, as well as determine whether additional candidate modifiers can modulate FXTAS pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS051630-14
Application #
9687218
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Riddle, Robert D
Project Start
2006-01-01
Project End
2024-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
14
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Cheng, Ying; Wang, Zhi-Meng; Tan, Weiqi et al. (2018) Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nat Neurosci 21:1689-1703
Yao, Bing; Li, Yujing; Wang, Zhiqin et al. (2018) Active N6-Methyladenine Demethylation by DMAD Regulates Gene Expression by Coordinating with Polycomb Protein in Neurons. Mol Cell 71:848-857.e6
Cheng, Ying; Li, Ziyi; Manupipatpong, Sasicha et al. (2018) 5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder. Hum Mol Genet 27:2955-2964
Yao, Bing; Jin, Peng (2018) A unique epigenomic landscape defines the characteristics and differentiation potentials of glioma stem cells. Genome Biol 19:51
Feng, Hao; Jin, Peng; Wu, Hao (2018) Disease prediction by cell-free DNA methylation. Brief Bioinform :
Sun, Xiaobo; Gao, Jingjing; Jin, Peng et al. (2018) Optimized distributed systems achieve significant performance improvement on sorted merging of massive VCF files. Gigascience 7:
Kim, Hyerim; Wang, Xudong; Jin, Peng (2018) Developing DNA methylation-based diagnostic biomarkers. J Genet Genomics 45:87-97
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
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, 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

Showing the most recent 10 out of 76 publications