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.
Highlights
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG triplet repeat expansion within the 5 UTR of FMR1
Along with the presence of FMR1 mRNA in ubiquitin-positive intranuclear inclusions of FXTAS patient brains, these observations point to a toxic RNA gain-of-function mechanism for FXTAS pathogenesis, which could lead to sequestration of various rCGG repeat-binding proteins (Tassone et al, 2004)
We demonstrated that hnRNP A2/B1 may regulate the activation of gypsy by recruiting heterochromatin protein 1 (HP1) for transposon silencing
Summary
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG triplet repeat expansion within the 5 UTR of FMR1. Individuals possess between 5 and 54 CGG repeats, and full mutation CGG repeats greater than 200 lead to the neurodevelopmental disease fragile X syndrome (FXS), which results from the excessive methylation of FMR1 and loss of FMRP protein (Kremer et al, 1991; Verkerk et al, 1991; Hagerman and Hagerman, 2002; Colak et al, 2014). Individuals with 55–200 CGG repeats are referred to as premutation carriers (Cronister et al, 2008). Over a third of male expanded CGG repeat premutation carriers develop FXTAS later in adulthood (Jacquemont et al, 2004), whereas female premutation carriers may develop fragile X-associated primary ovarian insufficiency (FXPOI; Rodriguez-Revenga et al, 2009). Random X-inactivation is believed to protect female carriers from developing FXTAS, leading to relatively few female FXTAS patients (Hagerman et al, 2004; Zühlke et al, 2004; Coffey et al, 2008)
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