Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

Cabal-Herrera, Ana María; Tassanakijpanich, Nattaporn; Salcedo-Arellano, María Jimena; Hagerman, Randi J.

doi:10.3390/ijms21124391

Cited by 75 publications

(60 citation statements)

References 174 publications

(298 reference statements)

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“…The Fmrp, another RBP, can bind to ribosomes and regulate ribosome stalling [16][17][18] . The depletion of Fmr1, as observed in Fragile X syndrome, results in increased protein synthesis that is linked to synaptic and behavioral defects and that can also elicit the neurodegenerative phenotype in Fragile X-associated tremor/ataxia syndrome 19,20 . Deficits in rescuing ribosome stalling may also promote neurodegeneration 2,21 .…”

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confidence: 99%

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

et al. 2021

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The polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis in mouse HD striatal neuronal cells. Depletion of mHtt enhances protein synthesis and increases the speed of ribosomal translocation, while mHtt directly inhibits protein synthesis in vitro. Fmrp, a known regulator of ribosome stalling, is upregulated in HD, but its depletion has no discernible effect on protein synthesis or ribosome stalling in HD cells. We found interactions of ribosomal proteins and translating ribosomes with mHtt. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seq indicates a widespread shift in ribosome occupancy toward the 5′ and 3′ end and unique single-codon pauses on selected mRNA targets in HD cells, compared to controls. Thus, mHtt impedes ribosomal translocation during translation elongation, a mechanistic defect that can be exploited for HD therapeutics.

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confidence: 99%

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

et al. 2021

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“…Approximately 30-40% of male and 8-16% of female PM carriers will develop FXTAS, with onset of initial symptoms typically beginning in males in their early 60's (Leehey et al, 2007;Hagerman and Hagerman, 2016). Symptoms of FXTAS include intention tremor, gait ataxia, parkinsonism, neuropathy, white matter disease, and cognitive decline (Hall et al, 2014;Hagerman and Hagerman, 2016;Kong et al, 2017;Cabal-herrera et al, 2020). The principal neuropathological feature of FXTAS is the presence of generally solitary intranuclear inclusions in both neurons and astrocytes within the central nervous system (CNS) (Greco et al, 2002(Greco et al, , 2006Garcia-Arocena et al, 2009;Martínez Cerdeño et al, 2018), as well as in diverse non-CNS tissues (Greco et al, 2007;Hunsaker et al, 2011), mitochondrial dysfunction (Ross-Inta et al, 2010;Napoli et al, 2011;Kaplan et al, 2012;Cabal-herrera et al, 2020), microglia activation and senescence (Martínez Cerdeño et al, 2018), iron deposition (Ariza et al, 2018), and dysregulation of neuronal Ca 2+ (Robin et al, 2017;Hagerman et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

Holm

Herren

Taylor

et al. 2021

Front. Mol. Biosci.

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Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation CGG-repeat expansions (55–200 repeats) in the 5′ non-coding portion of the fragile X mental retardation 1 (FMR1) gene. Core features of FXTAS include progressive tremor/ataxia, cognitive decline, variable brain volume loss, and white matter disease. The principal histopathological feature of FXTAS is the presence of central nervous system (CNS) and non-CNS intranuclear inclusions.Objective: To further elucidate the molecular underpinnings of FXTAS through the proteomic characterization of human FXTAS cortexes.Results: Proteomic analysis of FXTAS brain cortical tissue (n = 8) identified minor differences in protein abundance compared to control brains (n = 6). Significant differences in FXTAS relative to control brain predominantly involved decreased abundance of proteins, with the greatest decreases observed for tenascin-C (TNC), cluster of differentiation 38 (CD38), and phosphoserine aminotransferase 1 (PSAT1); proteins typically increased in other neurodegenerative diseases. Proteins with the greatest increased abundance include potentially novel neurodegeneration-related proteins and small ubiquitin-like modifier 1/2 (SUMO1/2). The FMRpolyG peptide, proposed in models of FXTAS pathogenesis but only identified in trace amounts in the earlier study of FXTAS inclusions, was not identified in any of the FXTAS or control brains in the current study.Discussion: The observed proteomic shifts, while generally relatively modest, do show a bias toward decreased protein abundance with FXTAS. Such shifts in protein abundance also suggest altered RNA binding as well as loss of cell–cell adhesion/structural integrity. Unlike other neurodegenerative diseases, the proteome of end-stage FXTAS does not suggest a strong inflammation-mediated degenerative response.

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“…R-loop formation at the FMR1 locus has also been proposed as a source of pathology in PM carriers [49,119] as illustrated in Figure 2B. R-loops are prone to single-stranded breaks and DSBs resulting from clustered single-stranded breaks [120].…”

Section: Pathology In Pm Carriersmentioning

confidence: 98%

(Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology in FMR1 Disorders

Zhao

Usdin

2021

IJMS

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Fragile X-related disorders (FXDs), also known as FMR1 disorders, are examples of repeat expansion diseases (REDs), clinical conditions that arise from an increase in the number of repeats in a disease-specific microsatellite. In the case of FXDs, the repeat unit is CGG/CCG and the repeat tract is located in the 5′ UTR of the X-linked FMR1 gene. Expansion can result in neurodegeneration, ovarian dysfunction, or intellectual disability depending on the number of repeats in the expanded allele. A growing body of evidence suggests that the mutational mechanisms responsible for many REDs share several common features. It is also increasingly apparent that in some of these diseases the pathologic consequences of expansion may arise in similar ways. It has long been known that many of the disease-associated repeats form unusual DNA and RNA structures. This review will focus on what is known about these structures, the proteins with which they interact, and how they may be related to the causative mutation and disease pathology in the FMR1 disorders.

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Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

Cited by 75 publications

References 174 publications

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

(Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology in FMR1 Disorders

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