Abstract

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. Several lines of evidence, including ours, have led to the proposal of an RNA-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. Through small molecule screen, we have identified potent small molecules that could suppress rCGG-mediated neurodegeneration in FXTAS Drosophila model. In this translational R21 proposal, we plan to further test these compounds in FXTAS mouse model and identify additional small molecules that could suppress rCGG- mediated neuronal toxicity.

Public Health Relevance

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. We have identified small molecules that could suppress rCGG- mediated neurodegeneration using FXTAS Drosophila model. In this translational R21 application, we plan to further validate these compounds in FXTAS mouse model, which could provide potential therapeutic interventions for FXTAS.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS067461-02
Application #
8144846
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Riddle, Robert D
Project Start
2010-09-17
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$192,813
Indirect Cost

  Institution

Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

Lumaban, Jeannette G; Nelson, David L (2015) The Fragile X proteins Fmrp and Fxr2p cooperate to regulate glucose metabolism in mice. Hum Mol Genet 24:2175-84
Poidevin, Mickael; Zhang, Feiran; Jin, Peng (2015) Small-molecule screening using Drosophila models of human neurological disorders. Methods Mol Biol 1263:127-38
Galloway, Jocelyn N; Shaw, Chad; Yu, Peng et al. (2014) CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome. Hum Mol Genet 23:5906-15
Huang, Haidong; Li, Yujing; Szulwach, Keith E et al. (2014) AGO3 Slicer activity regulates mitochondria-nuage localization of Armitage and piRNA amplification. J Cell Biol 206:217-30
Xu, Zihui; Poidevin, Mickael; Li, Xuekun et al. (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A 110:7778-83
Li, Yujing; Lin, Li; Li, Zigang et al. (2012) Iron homeostasis regulates the activity of the microRNA pathway through poly(C)-binding protein 2. Cell Metab 15:895-904
Tan, Huiping; Poidevin, Mickael; Li, He et al. (2012) MicroRNA-277 modulates the neurodegeneration caused by Fragile X premutation rCGG repeats. PLoS Genet 8:e1002681
Li, Yujing; Jin, Peng (2012) RNA-mediated neurodegeneration in fragile X-associated tremor/ataxia syndrome. Brain Res 1462:112-7
Qurashi, Abrar; Li, Xuekun; Jin, Peng (2012) Fragile X mental retardation protein and stem cells. Results Probl Cell Differ 54:157-64
Qurashi, Abrar; Liu, Huijie; Ray, Laurie et al. (2012) Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila. Hum Mol Genet 21:2068-75

Showing the most recent 10 out of 20 publications