Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

ObjectiveTo explore the association of a splice variant of theantisense fragile X mental retardation 1(ASFMR1) gene, loss offragile X mental retardation 1(FMR1) AGG interspersions andFMR1CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).MethodsPremutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression ofASFMR1transcript/splice variant 2 (ASFMR1-TV2), nonsplicedASFMR1, totalASFMR1, andFMR1messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.ResultsPremutation men and women both with and without FXTAS had higherASFMR1-TV2 levels compared with NC men and women (n = 135,135,p< 0.0001), andASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevatedASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined).ConclusionsThis study found elevated levels ofASFMR1-TV2and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.

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Lack of a Clear Behavioral Phenotype in an Inducible FXTAS Mouse Model Despite the Presence of Neuronal FMRpolyG-Positive Aggregates

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.599101 ◽

2020 ◽

Vol 7 ◽

Author(s):

Saif N. Haify ◽

Ruchira S. D. Mankoe ◽

Valerie Boumeester ◽

Esmay C. van der Toorn ◽

Rob F. M. Verhagen ◽

...

Keyword(s):

Mouse Model ◽

Rna Binding ◽

Neurodegenerative Disorder ◽

Rna Binding Proteins ◽

Fragile X ◽

Brain Regions ◽

Intranuclear Inclusions ◽

Behavioral Deficits ◽

Cgg Repeat ◽

Progressive Cerebellar Ataxia

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder caused by a 55–200 CGG repeat expansion in the 5′ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene. FXTAS is characterized by progressive cerebellar ataxia, Parkinsonism, intention tremors and cognitive decline. The main neuropathological hallmark of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes throughout the brain. The molecular pathology of FXTAS involves the presence of 2 to 8-fold elevated levels of FMR1 mRNA, and of a repeat-associated non-AUG (RAN) translated polyglycine peptide (FMRpolyG). Increased levels of FMR1 mRNA containing an expanded CGG repeat can result in cellular toxicity by an RNA gain-of-function mechanism. The increased levels of CGG repeat-expanded FMR1 transcripts may create RNA foci that sequester important cellular proteins, including RNA-binding proteins and FMRpolyG, in intranuclear inclusions. To date, it is unclear whether the FMRpolyG-positive intranuclear inclusions are a cause or a consequence of FXTAS disease pathology. In this report we studied the relation between the presence of neuronal intranuclear inclusions and behavioral deficits using an inducible mouse model for FXTAS. Neuronal intranuclear inclusions were observed 4 weeks after dox-induction. After 12 weeks, high numbers of FMRpolyG-positive intranuclear inclusions could be detected in the hippocampus and striatum, but no clear signs of behavioral deficits related to these specific brain regions were found. In conclusion, the observations in our inducible mouse model for FXTAS suggest a lack of correlation between the presence of intranuclear FMRpolyG-positive aggregates in brain regions and specific behavioral phenotypes.

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CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome

Neuron ◽

10.1016/j.neuron.2013.07.008 ◽

2013 ◽

Vol 79 (2) ◽

pp. 402 ◽

Cited By ~ 1

Author(s):

Peter K. Todd ◽

Seok Yoon Oh ◽

Amy Krans ◽

Fang He ◽

Chantal Sellier ◽

...

Keyword(s):

Fragile X ◽

Cgg Repeat ◽

Ataxia Syndrome

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Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

Brain Sciences ◽

10.3390/brainsci9030052 ◽

2019 ◽

Vol 9 (3) ◽

pp. 52 ◽

Cited By ~ 2

Author(s):

Xiaonan Zhao ◽

Inbal Gazy ◽

Bruce Hayward ◽

Elizabeth Pintado ◽

Ye Hwang ◽

...

Keyword(s):

Mouse Model ◽

Mouse Models ◽

Molecular Basis ◽

Fragile X ◽

Fmr1 Gene ◽

Repeat Instability ◽

Cgg Repeat ◽

Repeat Tract ◽

Exon 1 ◽

Clinical Conditions

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.

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Fragile X-associated tremor/ataxia syndrome: Intrafamilial variability and the size of theFMR1 premutation CGG repeat

Movement Disorders ◽

10.1002/mds.21347 ◽

2007 ◽

Vol 22 (6) ◽

pp. 866-870 ◽

Cited By ~ 13

Author(s):

Leonardo P. Capelli ◽

Márcia R. R. Gonçalves ◽

Fernando Kok ◽

Cláudia C. Leite ◽

Ricardo Nitrini ◽

...

Keyword(s):

Fragile X ◽

Cgg Repeat ◽

Intrafamilial Variability ◽

Ataxia Syndrome

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CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome

Neuron ◽

10.1016/j.neuron.2013.03.026 ◽

2013 ◽

Vol 78 (3) ◽

pp. 440-455 ◽

Cited By ~ 257

Author(s):

Peter K. Todd ◽

Seok Yoon Oh ◽

Amy Krans ◽

Fang He ◽

Chantal Sellier ◽

...

Keyword(s):

Fragile X ◽

Cgg Repeat ◽

Ataxia Syndrome

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

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.600840 ◽

2021 ◽

Vol 7 ◽

Author(s):

Katharine Nichole Holm ◽

Anthony W. Herren ◽

Sandra L. Taylor ◽

Jamie L. Randol ◽

Kyoungmi Kim ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Structural Integrity ◽

Rna Binding ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Protein Abundance ◽

Cgg Repeat ◽

Phosphoserine Aminotransferase ◽

Brain Volume Loss ◽

Ataxia Syndrome

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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