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Fragile X-Associated Tremor/Ataxia Syndrome: From Molecular Pathogenesis to Development of Therapeutics

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Last modified
  • 03/03/2025
Type of Material
Authors
    Ha Eun Kong, Emory UniversityJuan Zhao, Central South UniversityShunliang Xu, 2nd Hospital of Shandong UniversityPeng Jin, Emory UniversityYan Jin, Jilin University
Language
  • English
Date
  • 2017-05-05
Publisher
  • Frontiers Media
Publication Version
Copyright Statement
  • © 2017 Kong, Zhao, Xu, Jin and Jin.
License
Final Published Version (URL)
Title of Journal or Parent Work
ISSN
  • 1662-5102
Volume
  • 11
Grant/Funding Information
  • This study was supported in part by grants from the National Institutes of Health (NS051630, NS079625 and NS091859 to PJ).
Abstract
  • Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a premutation CGG repeat expansion (55–200 repeats) within the 5′ UTR of the fragile X gene (FMR1). FXTAS is characterized by intension tremor, cerebellar ataxia, progressive neurodegeneration, parkinsonism and cognitive decline. The development of transgenic mouse and Drosophila melanogaster models carrying an expanded CGG repeat has yielded valuable insight into the pathophysiology of FXTAS. To date, we know of two main molecular mechanisms of this disorder: (1) a toxic gain of function of the expanded CGG-repeat FMR1 mRNA, which results in the binding/sequestration of the CGG-binding proteins; and (2) CGG repeat-associated non-AUG-initiated (RAN) translation, which generates a polyglycine peptide toxic to cells. Besides these CGG-mediated mechanisms, recent studies have shed light on additional mechanisms of pathogenesis, such as the antisense transcript ASFMR1, mitochondrial dysfunction, DNA damage from R-loop formation and 5-hydroxymethylcytosine (5hmC)-mediated epigenetic modulation. Here we summarize the recent progress towards understanding the etiology of FXTAS and provide an overview of potential treatment strategies.
Author Notes
Keywords
Research Categories
  • Biology, Genetics
  • Health Sciences, Opthamology

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