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

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.

Age‐ and CGG repeat‐related slowing of manual movement in fragile X carriers: A prodrome of fragile X‐associated tremor ataxia syndrome?

“…There are 2 known molecular mechanisms of this disorder: (1) a toxic gain of function of the expanded CGG-repeat FMR1 messenger ribonucleic acid (mRNA), which results in the sequestration of the CGGbinding proteins contributing to inclusion formations in neurons and astrocytes and (2) CGG repeat-associated non-AUG-initiated translation, which generates a peptide toxic to cells. 3 Also, recent studies have shed light on additional potential mechanisms of pathogenesis such as the antisense transcript FMR1 (ASFMR1) and mitochondrial dysfunction. 4,5 Although the clinical, neuropathological, and neuroanatomical features of FXTAS have been described extensively, the risk and protective factors for development of the disease are largely unknown.…”

Curcumin Regulates the r(CGG)exp RNA Hairpin Structure and Ameliorate Defects in Fragile X-Associated Tremor Ataxia Syndrome

“…It is well known that expansion of CGG repeats in the 5 UTR of mutant FMR1 transcripts causes FXTAS (Hoem et al, 2011;Kong et al, 2017). Previously, it was reported that CGG repeat DNA and RNA sequences form 1 × 1 GG internal hairpin and tetraplex structure (Khateb et al, 2004;Zumwalt et al, 2007).…”

Repeat-associated non-ATG (RAN) translation

“…Additional approaches, including the use of small molecules, are being applied to repeat expansion disorders. These strategies include blocking transcription (173,174) and targeting the expansion RNAs (175)(176)(177)(178)(179)(180)(181) or downstream cellular processes (122,(182)(183)(184)(185)(186). Targeting nucleocytoplasmic transport defects associated with repeat diseases has also been shown to be neuroprotective in both C9ORF72-ALS models (86,187) and HD mouse models (145).…”