Evidence for RNA-Mediated Toxicity in the Fragile X-Associated Tremor/Ataxia Syndrome

Abstract

Fragile X premutation carriers are at risk for developing a late-onset, progressive neurodegenerative disorder termed fragile X-associated tremor/ataxia syndrome (FXTAS). A growing body of evidence suggests the characteristic excess CGG repeat containing FMR1 mRNA observed in premutation carriers is pathogenic and leads to clinical features of FXTAS. The current model suggests premutation mRNA transcripts can induce the formation of intranuclear inclusions by the sequestration of RNA-binding proteins and other proteins. The sequestered proteins are prevented from performing their normal functions, which is thought to lead to the neuropathology-observed FXTAS. This paper discusses the existing evidence that microsatellite expansions at the level of RNA play a role in the disease pathogenesis of FXTAS and some of the approaches that may uncover downstream effects of expanded riboCGG expression. KeywordsFXTAS; intranuclear inclusion; neurodegeneration; premutation allele; riboCGG-mediated toxicity; RNA-binding protein The X-linked FMR1 gene has a polymorphic CGG repeat located in its 5′ untranslated region (UTR). The alleles of the FMR1 gene can be grouped into three distinct classes depending on the size of the repeat. Among individuals in the general population, repeat length ranges between five and 54 triplets, with the majority of X chromosomes carrying either 29 or 30 repeats. A second allele class is known as the full mutation, wherein upon expansion of the CGG repeat tract to more than 200 triplets, the repeat sequence itself and an adjacent CpG island become hypermethylated and associated histones are modified. As a result, FMR1 transcription is silenced [1][2][3][4][5][6][7]. Thus, fragile X syndrome (FXS), the most commonly inherited form of mental retardation, results from the loss of function of FMR1. The mechanism for CGG repeat expansion is still under investigation, however, evidence suggests the expansion to the full mutation occurs in female gametes [8,9]. Male and female carriers of FXS represent the †Author for correspondence: Baylor College of Medicine, Department of Molecular & Human Genetics, One Baylor Plaza, Room 902EA, Houston, TX 77030, USA, Tel.: +1 713 798 4787, Fax + 1 713 798 1116, nelson@bcm.tmc.edu. For reprint orders, please contact: reprints@futuremedicine.com Financial & competing interests disclosure:The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. The most common clinical features of FXTAS include a progressive action tremor with ataxia. NIH Public AccessMore advanced or severe cases may show a progressive decline in cognition that ranges from executive and memory deficits to dementia [13]. FXTAS patients may also exhibit psychological symptoms such as depres...

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…Supporting the significance of the G-Qs, FMRP is capable of binding transcripts containing them (Darnell et al 2001;Vasilyev et al 2015), which can facilitate their translocation, in some cases, to synapses (Zhang et al 2014;Stefanovic et al 2015). In FXTAS patients, FMR1 is not completely silenced, and the expansion is actively transcribed into a repeat-containing RNA that has been reported to bind multiple RBPs, such as hnRNP A2/B1, MBNL1 (Iwahashi et al 2006), Sam68 (Sellier et al 2010), Drosha, DGCR8 (Sellier et al 2013), and more (Galloway and Nelson 2009). Evidence for the functional significance of this binding to human disease is somewhat limited; however, overexpression of hnRNP A2/B1 and CUGBP1 (Sofola et al 2007) or Pur-α ) in Drosophila models of FXTAS can suppress the neurodegenerative phenotypes.…”

Three Faces of Fragile X

“…Galloway 5 supports the need to identify carriers of the FMR1 mutation given the high prevalence of this mutation in the general population with the risk, as a carrier, of developing clinical features of FXTAS.…”

Aspectos clínicos, moleculares y farmacológicos en los trastornos asociados a gen 1 del retraso mental del X frágil

“…De esta forma, se produce una acumulación de inclusiones ubiquitina positiva en los núcleos de las neuronas y glías del SNC 65 que contienen mRNA de FMR1 expandido y proteínas con motivos de unión a RNA que son secuestradas, afectando su función y produciendo neurodegeneración 66 . El número y tamaño de las inclusiones aumentan con la edad en paralelo con la progresión de la enfermedad en humanos 67 . Además, hay disfunción mitocondrial en fibroblastos y el tejido cerebral de portadores de PM, con incremento del estrés oxidativo y disminución de la traducción de proteínas mitocondriales 68 .…”