AUTHOR=Kong Ha Eun , Zhao Juan , Xu Shunliang , Jin Peng , Jin Yan 

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

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=11

YEAR=2017

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2017.00128

DOI=10.3389/fncel.2017.00128

ISSN=1662-5102

ABSTRACT=<p>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 (<italic>FMR1</italic>). FXTAS is characterized by intension tremor, cerebellar ataxia, progressive neurodegeneration, parkinsonism and cognitive decline. The development of transgenic mouse and <italic>Drosophila melanogaster</italic> 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 <italic>FMR1</italic> 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 <italic>ASFMR1</italic>, 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.</p>