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.

Keywords: CGG repeat; FXTAS pathogenesis; FXTAS therapeutics; RAN translation; RNA toxicity.

Figure 1

Illustration of the main mechanisms of Fragile X-associated tremor/ataxia syndrome (FXTAS) pathogenesis. During transcription of the FMR1 locus, the formation of RNA:DNA hybrid R-loops through GC interaction of the expanded CGG repeats (depicted by yellow bar) can activate the DNA damage response and result in DNA breaks and the accumulation of γH2AX. The two main mechanisms linked to FXTAS pathology are post-transcriptional. In the RNA toxicity mechanism, RNA-binding proteins (RBPs) are sequestered by the expanded CGG repeats, such as h2RNP A2/B1, Pur α, Sam68, TDP43 and DGCR8; these are illustrated together for figurative purposes but do not necessarily form a complex simultaneously. In the RAN protein toxicity mechanism, the expanded CGG repeat induces AUG-independent RAN translation of FMRpolyG, which is found to form inclusions in patient brains as well as animal models of FXTAS. Other mechanisms not shown in this figure include the antisense transcript ASFMR1, mitochondrial dysfunction and 5hmC-mediated epigenetic modulation in FXTAS.

Figure 2

Potential therapeutic strategies for FXTAS. To date, there are no treatments available for FXTAS. Therapeutic strategies explored include targeting the RBP sequestration mechanism of FXTAS pathogenesis, such as via the use of small-molecule inhibitors that bind to CGG hairpins with high affinity, thereby reducing the sequestration of the RBPs (Disney et al., 2012). Other potential targets include the mTOR inhibitor rapamycin, phospholipase A2 (PLA2) inhibitors, an mGluR antagonist (MPEP) and a GABA agonist (allopregnanolone).