Molecular Pathophysiology of Fragile X-Associated Tremor/Ataxia Syndrome and Perspectives for Drug Development

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder manifesting in carriers of 55 to 200 CGG repeats in the 5' untranslated region (UTR) of the fragile X mental retardation gene (FMR1). FXTAS is characterized by enhanced FMR1 transcription and the accumulation of CGG repeat-containing FMR1 messenger RNA in nuclear foci, while the FMRP protein expression levels remain normal or moderately low. The neuropathological hallmark in FXTAS is the presence of intranuclear, ubiquitin-positive inclusions that also contain FMR1 transcript. Yet, the complete protein complement of FXTAS inclusions and the molecular events that trigger neuronal death in FXTAS remain unclear. In this review, we present the two most accepted toxicity mechanisms described so far, namely RNA gain-of-function and protein gain-of-function by means of repeat-associated non-AUG translation, and discuss current experimental and computational strategies to better understand FXTAS pathogenesis. Finally, we review the current perspectives for drug development with disease-modifying potential for FXTAS.

An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome

“…As splicing defects have been reported to occur in FXTAS disease ( Botta-Orfila et al., 2016 , Sellier et al., 2010 ), we decided to further investigate the recruitment of the splicing regulator TRA2A. B lymphocytes are often used for initial investigations because of their easy accessibility from blood samples from patients.…”

“…Indeed, the appearance of RNP condensates, often called inclusions or foci, is not only linked to ALS, Huntington’s disease, and MD but also other diseases, such as fragile X-associated tremor/ataxia syndrome (FXTAS) ( Tassone et al., 2004 , Sellier et al., 2017 ). The onset and development of FXTAS is currently explained by two main mechanisms ( Botta-Orfila et al., 2016 ): (1) RNA-mediated recruitment of proteins attracted by CGG trinucleotide repeats in the 5′ UTR of fragile X mental retardation protein ( FMR1 ) RNA and (2) aggregation of repeat-associated non-AUG (RAN) polyglycine peptides translated from the FMR1 5′ UTR (FMRpolyG) ( Todd et al., 2013 ). Previous work indicates that FMR1 inclusions contain specific proteins, such as HNRNP A2/B1, MBNL1, LMNA, and INA ( Iwahashi et al., 2006 ).…”

Of Men and Mice: Modeling the Fragile X Syndrome

“…It is noteworthy that pre-mutation carriers often develop a neurodegenerative disorder called the Fragile X-associated Tremor/Ataxia Syndrome (FXTAS, Figure 2 ), which presents with neurodegeneration, parkinsonism and brain atrophy, and which is associated with primary ovarian insufficiency in females (reviewed in Botta-Orfila et al, 2016 ; Hagerman and Hagerman, 2016 ). FXTAS is believed to arise from a toxicity of elongated mRNA transcripts and/or of a cryptic FMR1 protein derived from CGG repeat triggered non-ATG translation (Handa et al, 2005 ; Hashem et al, 2009 ; Chen et al, 2010 ; Todd et al, 2013 ).…”

In silico, in vitro, and in vivo Approaches to Identify Molecular Players in Fragile X Tremor and Ataxia Syndrome

“…This will allow us to better understand this complex neurological disorder and also to be used for drug development in the future. At present, the onset and development of FXTAS is explained by two main mechanisms (Botta-Orfila et al, 2016): (i) RNAmediated sequestration, and subsequent inactivation, of proteins attracted by the CGG trinucleotide repeats in the 5 UTR region of FMR1 RNA and (ii) toxic aggregation of Repeat-Associated Non-AUG (RAN) polyglycine peptides translated from the FMR1 5 UTR (FMRpolyG; Figure 1). Previous work indicates that FMR1 RNA forms aggregates containing specific proteins such as HNRNP A2/B1, MBNL1, LMNA, and INA (Iwahashi et al, 2006).…”